An
investigational
factor
XIa
inhibitor
did
not
reduce
the
risk
of
recurrent
cardiovascular
(CV)
events
in
patients
with
a
recent
acute
coronary
syndrome
(ACS)
event
on
top
of
antiplatelet
therapy,
although
there
was
no
increase
in
the
risk
for
major
bleeding
with
treatment,
according
to
the
LIBREXIA
ACS
trial.
The
phase
III
results
showed
that
for
the
primary
efficacy
outcome
—
a
composite
of
CV
death,
myocardial
infarction,
or
ischemic
stroke
evaluated
in
a
time-to-event
analysis
—
one
of
these
events
occurred
in
384
patients
(5.4%)
in
the
milvexian
group
and
365
patients
(5.1%)
in
the
placebo
group
(HR
1.05,
95%
CI
0.91-1.21,
P=0.50)
after
a
median
follow
up
of
12.2
months.
LIBREXIA
ACS
was
presented
at
the
European
Society
of
Cardiology
(ESC)
Congress
in
Munich,
Germany.
The
results
were
published
simultaneously
in
the
New
England
Journal
of
Medicine.
Milvexian’s
developer
suspended
LIBREXIA
ACS
in
November
2025,
and
issued
an
update
disclosing
that,
based
on
an
interim
analysis,
the
trial
was
“unlikely
to
meet
the
primary
efficacy
endpoint.”
The
data
and
safety
monitoring
board
(DSMB)
recommended
halting
the
trial
for
futility,
according
to
the
update.
But
study
author
P.
Gabriel
Steg,
MD,
of
Bichat-Claude
Bernard
Hospital
and
Paris
Diderot
University,
emphasized
that
there
was
some
“good
news:”
Milvexian
did
not
increase
the
primary
safety
outcome,
Bleeding
Academic
Research
Consortium
(BARC)
type
3c
or
5
bleeding
indicating
intracranial
or
intraocular
bleeding
that
compromises
vision
or
fatal
bleeding,
or
any
other
measures
of
major
bleeding
in
the
trial.
BARC
type
3c
or
5
bleeding
occurred
in
23
patients
(0.3%)
in
the
milvexian
group
and
in
22
patients
(0.3%)
in
the
placebo
group
(P=0.88).
“Why
is
this
important
in
terms
of
safety?
Because
milvexian
is
currently
being
evaluated
in
two
other
large
trials,
one
in
atrial
fibrillation,
and
one
in
secondary
stroke
prevention,”
Steg
noted,
“so
that
safety
is
an
important
feature.”
Those
phase
III
trials,
LIBREXIA
AF
and
LIBREXIA
STROKE,
are
ongoing.
The
DSMB
had
“recommended
these
trials
continue
as
planned,
with
topline
data
expected
in
2026,”
per
the
developer.
ESC
discussant
Marc
S.
Sabatine,
MD,
of
Brigham
and
Women’s
Hospital
in
Boston,
pointed
out
that
the
high
rate
of
revascularization
after
ACS
in
this
study,
at
92%
of
patients,
and
the
high
use
of
prolonged
dual
antiplatelet
therapy
(DAPT)
may
have
made
it
more
difficult
to
see
a
benefit
with
treatment.
“Nonetheless,
the
results
were
clear,”
Sabatine
said.
“There
was
no
benefit
for
milvexian
in
this
study.”
Even
though
it
was
stopped
early,
the
95%
CIs
“are
sufficiently
narrow
that
it’s
unlikely
that
we’re
missing
a
clinically
meaningful
benefit
with
this
drug,
at
this
dose,
for
these
outcomes
in
this
particular
population,
and
for
the
duration
of
treatment.”
The
low
bleeding
risk
was
positive,
but
also
calls
into
question
how
efficacious
the
drug
actually
is,
Sabatine
said.
Still,
another
novel
factor
XIa
inhibitor,
asundexian,
was
ineffective
in
atrial
fibrillation
compared
to
apixaban
(Eliquis),
but
effective
against
placebo
for
secondary
stroke
prevention.
“The
optimal
degree
of
factor
XI
or
XIa
inhibition
that
is
needed
in
different
patient
populations,
I
think
that
remains
undefined,
and
therefore,
there’s
much
more
to
be
learned
from
ongoing
trials,
testing
other
doses,
and
other
drugs,”
he
concluded.
Factor
XI
is
essential
for
thrombosis,
but
not
hemostasis,
raising
hope
that
inhibitors
of
this
factor
may
produce
a
safe
series
of
anticoagulants,
Steg
noted.
LIBREXIA
ACS
compared
25
mg
of
milvexian
twice
daily,
added
to
standard
antiplatelet
therapy
within
7
days
of
an
ACS
event,
to
placebo.
The
choice
of
antiplatelet
therapy
was
left
to
the
investigators,
either
DAPT
for
more
than
90
days,
DAPT
for
less
than
90
days,
or
single
platelet
therapy,
and
randomization
was
stratified
by
antiplatelet
therapy.
The
planned
interim
analysis
was
based
on
556
adjudicated
efficacy
endpoints,
at
which
time
the
trial
was
terminated
for
futility,
the
researchers
noted.
A
total
of
14,194
patients
were
enrolled
from
almost
900
international
sites,
with
7,094
assigned
to
milvexian
and
7,100
to
placebo.
Patients
had
to
have
ACS
with
two
or
more
risk
factors,
and
more
than
half
had
three
risk
factors,
Steg
noted,
making
them
a
group
at
increased
risk.
Despite
background
therapy
and
percutaneous
coronary
intervention
with
prolonged
DAPT,
plus
the
majority
of
patients
receiving
more
potent
P2Y12
inhibitors,
“the
incidence
of
MACE
[major
adverse
CV
events]
was
high,
and
there
remains
an
unmet
need,”
he
concluded.
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