ESC Congress FA eBook 2016 - 11A

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2016

The
Expanding
Role of of
NonThe
Landscape
The Changing
Changing
Landscape
of Stroke
Stroke
Prevention
Bleeding
Prevention
and
Bleeding in
in AF
AF
Vitamin
K and
Anticoagulants

In
contrast
to 2rivaroxaban,
food
does
not CHADS
affect the
bioFigure
1.
DS -VASc Score
Better
Than
Score
Figure
1. CHA
CHA
2DS22-VASc Score Better Than CHADS22 Score
for
of
availability
of edoxaban
and offers once daily dosing
forRisk
RiskStratification
Stratification
ofThromboembolism
Thromboembolism
which is also not available
with apixaban.
About
50% of
CHA
CHA
CHADS
DS-VASc
-VASc==00
CHADS
DS-VASc
-VASc==11
edoxaban's elimination
renal
hepatic.
CHA
-VASc
==22 and 50%
CHA
DS
CHADS
DSis
-VASc
CHA
DS-VASc
-VASc==33
In
past
the
for
In the
the
past decade,
decade,
the landscape
landscape
for management
management
==00
CHADS
All NOACs areCHADS
substrates
of the P-glycoprotein
The
non-vitamin
K antagonist
anticoagulants
(NOACs)
of
of patients
patients with
with atrial
atrial fibrillation
fibrillation (AF)
(AF) has
has changed
changed
100%
100%
represent a substantial
advance intostroke
prevention inof transporter. Less than 10% of edoxaban is metabodramatically,
dramatically, particularly
particularly due
due to the
the emergence
emergence of
lized by CYP3A/4
reducing its potential for drug-drug
the
setting
of
atrial
fibrillation
(AF),
supplanting
improved
bleed98%
improved risk
risk stratification
stratification tools
tools for
for stroke
stroke and
andwarfableed98%
interactions.
The
concomitant use of inhibitors of
rin
thenovel
treatment
of choice inagents.
patients eligible for both
ing,
and
antithrombotic
ing,as
and
novel
antithrombotic
agents.
96%
96% requires a dose reduction for all of the
Gregory
of
Birmingham,
according
the Lip,
2016
Guidelines
for the
Gregory toY.H.
Y.H.
Lip, MD,
MD, University
University
ofManagement
Birmingham, P-glycoprotein
1
Birmingham,
United
Kingdom,
addressed
the
of
NOACs; for 94%
edoxaban the reduced dose is 30 mg, which
Birmingham,
United
Kingdom,
addressed
the use
use(ESC).
of risk
risk
of
AF from the
European
Society
of Cardiology
94%
stratification
tools
for
the
prevention
of
bleeding.
stratification
tools
forfor
thethis
prevention
ofstroke
strokeand
and
bleeding.
was shown to provide effective protection against
The
evidence
base
recommendation
has
been
He
importance
of
the
92%
Healso
alsoemphasized
emphasized
the
importance
ofbalancing
balancing
therisk
risk
of ischemic events
92%
in all trials.
enriched
with datathe
from
the largest
and longest
pro-of
stroke
and
bleeding
in
the
treatment
of
patients
with
AF.
stroke
and
bleeding
in
the
treatment
of
patients
with
AF.
Dose
reduction
for edoxaban is different to those
spective, randomized controlled trial of a NOAC,
0%
0%
The
The stroke
stroke risk
risk assessment
assessment tool
tool used
used most
most commonly
commonly
2
0
100
200
300
0
100 of edoxaban
200
300Europe must
of other NOACs; the dose
in
namely,
the ENGAGE which
AF-TIMI 48initially
trial with edoxaban.
is
Days
is the
the CHADS
CHADS22 score,
score, which was
was initially developed
developed as
as aa
DaysFrom
FromDischarge
Discharge
be reduced (30 mg once daily) in the setting of moderAs
a class,
the NOACsindex
provide
more effective
protecstroke
risk
to
the
stroke
stroke
risk assessment
assessment
index
to predict
predict
the risk
risk of
of
stroke
1
Olesen
ofofthe
score
stratification
renal
impairment
(creatinine
clearance
OlesenJB
JBetetal.
al.The
Thevalue
value
theCHA2DS2-VASc
CHA2DS2-VASc
scorefor
forrefining
refiningstroke
strokerisk
risk
stratificationin
in
tion
againstwith
stroke
and systemic
embolic
(SEE)isis ate-to-severe
in
nonvalvular
AF.
this
in patients
patients
with
nonvalvular
AF.1 However,
However,events
this score
score
patients
patientswith
withatrial
atrialfibrillation
fibrillationwith
withaaCHADS2
CHADS2score
score0-1:
0-1:AAnationwide
nationwidecohort
cohortstudy.
study.Thromb
Thromb
Haemost.
With
permission
ml/min),
and
also
in from
patients
with lower body
largely
on
factors
stroke
identified
from
compared
warfarin,
and
also
significant
Haemost.2012;107:
2012;107:1172-1179.
1172-1179.
With
permission
fromSchattauer.
Schattauer.
largely based
basedwith
on risk
risk
factors for
for
stroke
identified
from 15-50
the
arms
trial
the non-warfarin
non-warfarin
arms of
of historical
historical
clinical
trial cohorts.
cohorts. weight (≤ 60 kg).* Although there is no specific antidote
reductions
in all-cause
mortalityclinical
and intracranial
3score
and
lone
AF
females],
or
score
The
CHADS
has
many
limitations,
including
the
22-VASc
andFXa
loneinhibitors,
AF[including
[including
females],
oraaCHA
CHA
DS
-VASc
score
2
The
CHADS
score
has
many
limitations,
including
the for
complete
reversal
has22DS
been
shown
hemorrhage.2
of
0
[males]
or
1
[females])
with
AF
who
do
not
require
fact
that
not
account
for
many
other
common
risk
of
0
[males]
or
1
[females])
with
AF
who
do
not
require
factNOACs
thatititdoes
does
not
account
for
many
other
common
risk
also are an attractive alternative because with a 50 IU/kg dose of 4-Factor prothrombin complex
antithrombotic
factors
for
stroke
that have
been
in
obserantithrombotic therapy.
therapy. This
This isis aa shift
shift from
from prior
prior practice
practice
factors
for
stroke
beenidentified
identified
inlarge
large
obser- concentrate.
of their ease of that
usehave
in clinical
practice,
compared
vational
guidelines,which
whichfocused
focusedon
onidentifying
identifyinghigh-risk
high-riskpatients.
patients.
vational cohort
cohort studies.
studies.22 Consequently,
Consequently, the
the CHA
CHA22DS
DS22-- guidelines,
with score
VKAs, which
require account
frequent monitoring
to
VASc
Patients with
with ≥≥11 additional
additional stroke
stroke risk
risk factors
factors should
should be
be
VASc score was
was developed
developed to
to account for
for factors
factors such
such as
as Patients
Safety and
Efficacy of Edoxaban
maintain
therapeutic
levels
(international
normalfemale
offeredoral
oralanticoagulation
anticoagulationto
toprevent
preventstroke.
stroke.88
female sex,
sex, age
age 65
65 to
to 74
74 years,
years, and
and coronary
coronary artery
artery disdis- offered
major
trials,
eachMD,
thePhD,
longest
and largestUniversity,
for their
ized
2.0-3.0)
and related
doseat
Raffaele
De
Caterina,
G.
ease.
This
risk
identifies
subjects
high
Raffaele
De
Caterina,
MD,
PhD,
G.d'Annunzio
d'Annunzio
University,
ease.ratio
This [INR]
risk score
score
identifies
subjects
atadjustments,
high risk
risk for
for Three
patient
populations,
have affirmed
theprovided
safety
Chieti,
G.
Foundation,
Pisa,
thromboembolism,
well
who
are
risk,
potential
drug-drugas
interactions,
and
limits
for
eating
Chieti,and
and
G.Monasterio
Monasterio
Foundation,
Pisa,Italy,
Italy,
provided
thromboembolism,
as
well as
as those
those
who
are at
at low
low
risk, specific
3,4
further
insight
how
guidelines
are
more
than
CHADS
and
efficacy
edoxaban.
The ENGAGE
AF-TIMI
48
further
insightofinto
into
howthe
thetreatment
treatment
guidelines
arebeing
being
moreaccurately
accurately
thanthe
the
CHADS22score
score(Figure
(Figure1).
1).3,4
vitamin
K-containing
foods.
implemented
in
clinical
practice,
focusing
on
data
from
the
There
is
considerable
overlap
of
risk
factors
that
preimplemented
in
clinical
practice,
focusing
on
data
from
the
There
is
considerable
overlap
of
risk
factors
that
preEdoxaban is approved in Europe for stroke pre- trial followed 21,105 patients with AF and a moderate
Prevention
of
thromboembolic
events
-
European
Registry
dict
stroke
and
bleeding.
Thus,
therapies
designed
to
Prevention
of
thromboembolic
events
-
European
Registry
dict
stroke
and
bleeding.
Thus,
therapies
designed
to
to high risk of stroke (CHADS2 score9 ≥ 2) for a median of
vention in patients with AF based on results from the
9
in
Fibrillation [PREFER
in
reduce
the
risk
of
stroke
(eg,
oral
anticoagulants)
inAtrial
Atrial
[PREFER
inAF].
AF].
reduce
the
risk
of
stroke
(eg,
novel
oral
anticoagulants)
2 novel
2.8
years.Fibrillation
It demonstrated
that
edoxaban had a simiENGAGE AF-TIMI 48 trial, and for the treatment of
Given
need
Given the
the high
high incidence
incidence of
of stroke
stroke in
in patients
patients with
with AF,
AF,
need to
to balance
balance the
the benefit
benefit from
from stroke
stroke prevention
prevention
lar efficacy
with well-managed anticoagulant
warfarin (median
venous the
thromboembolism
(VTE) HAS-BLED
and secondary preagainst
current ESC
ESC guidelines
guidelines recommend
recommend anticoagulant therapy
therapy
against the risk
risk of
of bleeding.
bleeding. The
The HAS-BLED score
score has
has current
time-in-therapeutic
range
[TTR] 68.4%),
with8,10
a 21%
vention
of VTE, based
resultsrisk
fromassessment
the Hokusai-VTE
been
as
bleeding
tool
forall
allof
ofpatients
patientswith
withAF,
AF,except
exceptthose
thoseat
atlow
lowrisk.
risk.8,10In
Inparparbeen developed
developed
as aa on
bleeding
risk
assessment
tool to
to for
4
5
reduction
in
the
primary
outcome
of
stroke
and
SEE
study,
of which
represent the
largest
Phase
3 AF.
studticular,
support
clinical
decision-making
for
patients
with
ticular, when
when adjusted-dose
adjusted-dose vitamin
vitamin KK antagonists
antagonists (VKAs;
(VKAs;
supportboth
clinical
decision-making
for
patients
with
AF.5
<2-3)
.001cannot
for noninferiority)
while
onAF
treatment.
In
INR
be
with
where
to
Prof
HAS-BLED
score
has
been
iesAccording
of a NOAC
AFLip,
andthe
VTE
respectively.
Now,
INR
2-3)
cannot
beused
usedin
inaapatient
patient
with
AF
wherean
anOAC
OAC
According
toin
Prof
Lip,
the
HAS-BLED
score
hasdata
been (P
isis recommended,
the
of
the
non-VKA
oral
shown
to
outperform
older
bleeding
the
intention-to-treat
analysis,
the
recommended,
the use
use
of one
one of
of
theprimary
non-VKAoutcome
oral antiantishownthe
toENSURE-AF
outperform trial
olderextends
bleeding
scores
and
the the
from
thescores
use of and
edoxacoagulants
(NOACs)
advised.
Furthermore,
OAC
Anticoagulation
and
Risk
in
Fibrillation
coagulants
(NOACs)
advised.
Furthermore,
where
OAC
Anticoagulation
and
Risk Factors
Factors
in Atrial
Atrial
Fibrillation was
reduced
by 13%isiswith
edoxaban
versuswhere
warfarin
ban
as a safe and
effective
alternative
to enoxaparin/
therapy
is
recommended,
one
of
the
NOACs
should
be
conscore
in
relation
to
predicting
the
risk
of
serious
bleeding.
5
therapy
is
recommended,
one
of
the
NOACs
should
be
conscore
in
relation
to
predicting
the
risk
of
serious
bleeding.
(P = .08 for superiority). Fatal bleeding was nearly 50%
warfarin in patients with AF undergoing cardioversion.
sidered
instead
of
adjusted-dose
VKA
(INR
2-3)
for
most
The
sidered
instead
of
adjusted-dose
VKA
(INR
2-3)
for
most
TheHAS-BLED
HAS-BLEDscore
scoreisiscurrently
currentlythe
theonly
onlyrisk
riskprediction
prediction less
with edoxaban versus warfarin (0.18% vs 0.33% per
model
patientswith
withnonvalvular
nonvalvularAF,
AF,based
basedon
onnet
netclinical
clinicalbenefit.
benefit.
model that
that reliably
reliably predicts
predicts intracranial
intracranial hemorrhage
hemorrhage patients
year,
respectively;
P = .003). the purpose of PREFER in AF
Clinical
of Edoxaban
6,7 Pharmacology
(ICH).
While
Asaaresult
resultof
ofthese
theseguidelines,
guidelines, the purpose of PREFER in AF
(ICH).6,7
While this
this risk
risk score
score can
can be
be used
used to
to identify
identify As
In the
ENGAGE AF-TIMI
48 trial,AF
25% of currently
the edoxaban
Edoxaban
simple,
once-daily
dosing, modifiable
a feature
was
subjects
risk
bleeding
and
was to
to describe
describe how
how patients
patients with
with AF are
are currently being
being
subjects at
atoffers
risk for
for
bleeding
and to
to identify
identify
modifiable
9
and
warfarin
groups
qualified
for
a
dose
reduction at
that
provides
of thrombin
generarisk
for
bleeding,
Prof
that
HASmanagedin
inEurope.
Europe.9
risk factors
factors
foreffective
bleeding,inhibition
Prof Lip
Lip noted
noted
that aa high
high
HAS- managed
and
7%aaduring
the study
period (20%
PREFER
was
prospective,
observational,
mulBLED
score
not
as
to
tion
for
> 24should
hours,
to
enoxaparin
1 mg/kg,
and randomization
PREFER in
in AF
AF
was
prospective,
observational,
mulBLED
score
should similar
not be
be used
used
as aa reason
reason
to withhold
withhold
ticenter
center
in
sites
in
European
oral
anticoagulant
(OAC)
since
the
risk
to impaired
renal function).
Yet,
efficacy
preticenter
center conducted
conducted
in 461
461
sites
in 77 was
European
oralpeak
anticoagulant
(OAC) therapy
therapy
since
the bleeding
bleeding
risk due
its
effect is achieved
within 1-2
hours
after
dosing
11
11 From January 2012 to January 2013, 7243 concountries.
may
the
benefit
countries.
From
2012 to January
7243 conmaynot
notoutweigh
outweigh
the
benefitof
ofanticoagulation
anticoagulation
therapy.
served
and
safetyJanuary
was enhanced
with 2013,
the reduced
because
of its rapid
absorption,
stated Dietmartherapy.
Trenk,
secutive
participants
(age
≥
18
years;
mean
age
=
years;
Prof
Lip
discussed
how
clinical
guidelines
have
also
secutive
participants
(age
≥
18
years;
mean
age
=
72
years;
Prof
Lip
discussed
how
clinical
guidelines
have
also
dose of edoxaban compared with warfarin, 72
stated
PhD, University Heart Center Freiburg, Bad Krozingen,
male
==60%)
with
aa history
of
AF
were
enrolled.
Of
the
evolved
in
the
past
decade
to
reflect
these
changes.
The
male
60%)
with
history
of
AF
were
enrolled.
Of
the
evolved
in
the
past
decade
to
reflect
these
changes.
The
Germany. Adherence also is improved with once daily Peter Verhamme, MD, PhD, University Hospitals
24%
had
persisEuropean
participants, 30%
30% had
had paroxysmal
paroxysmal AF,
AF,
24%
had
persisEuropeanSociety
Societyof
ofCardiology
Cardiology(ESC)
(ESC)guidelines
guidelinesnow
nowrecrec- participants,
Leuven,
Belgium (Table 1).6
dosing. identifying "truly low risk" patients (age < 65 years Leuven,
ommend
tent AF,
AF, 7%
7% had
had long-standing
long-standing persistent
persistent AF,
AF, and
and 39%
39% had
had
ommend identifying "truly low risk" patients (age < 65 years tent
A similar pattern of preserved efficacy and enhanced
There are some differences between edoxaban and
safety with the reduced dose of edoxaban, compared
the other NOACs. It has a high level of bioavailability
7
with warfarin,
was
found in the 2014.
Hokusai-VTE
study.
at
62%,
similar
to rivaroxaban
(66% when
fasting)
and theESC
This
Thispeer-reviewed
peer-reviewedarticle
articlewas
wasbased
basedon
onscientific-clinical
scientific-clinicalcontent
contentpresented
presentedatatthe
ESC(European
(EuropeanSociety
Societyof
ofCardiology)
Cardiology)Congress
Congress 2014.The
Thecontent
contentof
ofthis
thisarticle
article
was
developed
by
Express
and
Publications,
opinions
herein
necessarily
the
wasentirely
entirely
developed
byMD
MDConference
Conference
Express
andSAGE
SAGE(3-7%).
Publications,and
andthe
theOverall
opinionsexpressed
expressed
hereindo
do
not
necessarily
represent
those
theEuropean
European
recurrence
ofnot
VTE
was represent
3.2%
inthose
theofofedoxaban
higher
than
apixaban
(50%)
and
dabigatran
Society of Cardiology, nor of Daiichi Sankyo. The development of this article was supported by Daiichi Sankyo. This material is intended for educational purposes.
22

Proportionof
ofPatients
PatientsFree
Freeof
of
Proportion
Stroke/Thromboembolism
Stroke/Thromboembolism

Society of Cardiology, nor of Daiichi Sankyo. The development of this article was supported by Daiichi Sankyo. This material is intended for educational purposes.

This peer-reviewed article was based on scientific-clinical content presented at the ESC (European Society of Cardiology) Congress 2016. The content of this article was entirely developed
by Content Ed Net Medicom, and the opinions expressed herein do not necessarily represent those of the European Society of Cardiology, nor of Daiichi-Sankyo Europe GmbH. The
development of this article was supported by Daiichi-Sankyo Europe GmbH. This material is intended for educational purposes.

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