1° outcome: hemostatic efficacy = which was defined as;

(A) Hematoma expansion ≤ 35% at 12h

(B) increase in NIHSS ≤ 7 at 12h

(C) No rescue therapy 3-12h

Results hemostatic efficacy: 76.7% andexanet vs 64.6% usual care    

30 day mortality: no difference

30 day Modified Rankin Score ≤3: no difference

Thrombotic events: almost x2 with andexanet 10.3% vs 5.6% - statistically significant. Most were strokes and MI - not trivial.

The question you should ask: How does effective is hemostatic efficacy as a marker for patient outcomes?? Yes, we don’t want the brain bleed to get bigger but patients don’t care if the bleed gets bigger if they still die or if they still are in a coma for the rest of their life.

We know from warfarin that increase in hematoma expansion leads to worse outcomes (https://pubmed.ncbi.nlm.nih.gov/21346218/). We don’t have clear data on this for the DOACs. HOWEVER, just because an expanding hematoma leads to a bad outcome that does not mean that giving a medication to decrease hematoma expansion leads to better survival or improvement in disability.

In fact the randomized, double-blind, placebo-controlled trial we have that gave recombinant activated factor VII for acute intracerebrall hemorrhage showed that rFVIIa significantly reduced the growth of the hematoma but failed to improve survival or functional outcome at 90 days. https://pubmed.ncbi.nlm.nih.gov/19959538/

So we have a trial that shows improvement in hematoma expansion. It shows no difference in mortality or Rankin scale and demonstrates twice the rates of thrombotic events.

Bottom line-- ANNEXA-I does not show clear evidence of clinical benefit but there is definite evidence of harm. The logical argument for hematoma expansion as an outcome is compelling but not proven for patient oriented outcomes.