AHA bleeding related to warfarin and dabigatran 2013

Management and Outcomes of Major Bleeding during Treatment with Dabigatran or Warfarin
Ammar Majeed, Hun-Gyu Hwang, Stuart J. Connolly, John W. Eikelboom, Michael D. Ezekowitz,
Lars Wallentin, Martina Brueckmann, Mandy Fraessdorf, Salim Yusuf and Sam Schulman
Circulation. published online September 30, 2013;
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2013 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539

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DOI: 10.1161/CIRCULATIONAHA.113.002332

Management and Outcomes of Major Bleeding during Treatment with
Dabigatran or Warfarin

Running title: Majeed et al.; Dabigatran and major bleeding
Ammar Majeed, MD1; Hun-Gyu Hwang, MD2; Stuart J. Connolly, MD3; John W. Eikelboom,

MD3; Michael D. Ezekowitz, MD, ChB, Dphil4; Lars Wallentin, MD5; PhD, Martina Brueckmann,
MD6,7; Mandy Fraessdorf, PhD6; Salim Yusuf, MD, Dphil3; Sam Schulman, MD, PhD1,8
1

Coagulation Unit, Hematology Center, Karolinska University Hospital and Ka
Karolinska
aro
roli
l nsska IInstitute,
li
n ti
ns
titu
tute
tu
te
Stockholm, Sweden; 2Dept of Medicine, Soonchunhyang University Gumi’s Hospital, North
Kyungsang Province, South Korea; 3McMaster University, Population Health Research Institute,
Institute
Hami
Ha
Hamilton,
milt
mi
lton
lt
on, ON
on
ON,, Canada; 4Lankenau Medical
all C

Center,
enter, Thomas Jeffe
Jefferson
feers
rson
o Medical College,
Wynn
Wy
nnew
woo
od, P
A; 5Up
Uppsala
Upps
psal
a a Clinical
Clin
Cl
inic
icall Research
Res
esea
e rc
rchh Center
Ce r and
and Dept
Dep
ep
pt of
of Medical

Med
edical
al Sciences,
Scie
Sc
ienc
n es
es,, Up
Upps
Uppsala
sal
ala
Wynnewood,
PA;
6
University,
Un
Universi
ity
ty,, Uppsala,
Uppsal
Upp
psal
ala,
a, Sweden;
Swede
wede
den;
n; Bo
Boehringer

Boeh
e ring
eh
ri ger IIngelheim
nggellheim
im P
Pharma
harm
ha
rmaa Gm
Gmb
GmbH
bH & C
bH
Co
o KG
KG, In
Ingelheim,
nge
g lh
lhei
eim
ei
m,
Germany;
Germany; 7Facu
Faculty
culty off Medicine
cu
Meedicine

ic Ma
Mann
Mannheim,
nnnheim
m, Un
University
niv
verssitty of
of H
Heidelberg,
eiideelberrg,, Mannheim,
Man
nnheiim,
m, Germany;
Gerrmaany
y;
8
Dept
De
pt ooff Me
Med
Medicine,
dici
cinne, Mc
M
McMaster
Mast
Ma
s err U
st

University
nivvers
versiity
ity aand
nd
dT
Thrombosis
hrrom
mbo
osis and
and At
A
Atherosclerosis
herosscle
hero
scleero
rosi
siis Research
Re ear
Rese
arch
ch
h
Inst
In
Institute,
stit
itut
utte,
e, H

Hamilton,
amil
am
ilto
tonn, O
to
ON,
N, C
N,
Canada
anad
an
adaa
Ad
Add
dress for
for Correspondence:
Correspondence:
d
Address
Sam Schulman, MD
Thrombosis Service
HHS-General Hospital
237 Barton Street East
Hamilton, ON, L8L 2X2 Canada
Tel: 1-905-5270271, ext 44479
Fax: 1-905-5270271
E-mail:
Journal Subject Codes: Anticoagulants:[184] Coumarins, Anticoagulants:[185] Other
anticoagulants, Etiology:[5] Arrhythmias, clinical electrophysiology, drugs, Thrombosis:[173]

Deep vein thrombosis
1
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DOI: 10.1161/CIRCULATIONAHA.113.002332

Abstract:

BackgroundThe aim of this study was to compare the management and prognosis of major
bleeding in patients treated with dabigatran or warfarin.
Methods and ResultsTwo independent investigators reviewed bleeding reports from 1,034
individuals with 1,121 major bleeds enrolled in 5 phase III trials comparing dabigatran with
warfarin in 27,419 patients treated for 6 to 36 months. Patients with major bleeds on dabigatran
(n=627 of 16,755) were older, had lower creatinine clearance and more frequently used aspirin or
non-steroid anti-inflammatory agents than those on warfarin (n=407 of 10,002). The 30-day
mortality after the first major bleed tended to be lower in the dabigatran group (9.1%) than in the
warfarin group (13.0%; pooled odds ratio [OR] 0.68, 95% confidence interval [CI]: 0.46-1.01;
pp=0.057).
0.057). After adjustment for sex, age, weight, renal function and concomitant antithrombotic
ant
ntit
ithr
hrom
ombo
boti
tic
herapy, the pooled OR for 30-day mortality with dabigatran versus warfarin was
waas 0.66
0..66

6 (95%
(95
95%
% CI:
CI
therapy,
0.44-1.00; p=0.051). Major bleeds in dabigatran patients were more frequently treated with blood
ransf
sfus
usio
ionss ((423/696,
423/
3/69
3/
696, 61%) than bleeds in warf
far
arin
in patients (175/425
5, 42
42%; p<0.001) but less
transfusions
warfarin
(175/425,
fr
freq
equuent
eq
uen ly
y with
with plasma

plas
pl
asma
ma (dabigatran,
(da
dabi
b ga
gatr
tran
an,, 19.8%;
19.88%; warfarin,
19
war
arfa
faariin, 30.2%;
30.
0.2%
2%; p<0.001).
p<00.0
p<
0.001)
1).. Patients
Patie
ient
ntss who
who
frequently
ex
xperienced a bl
blee

eeed hhad
ad sh
horrteer st
tay
ays in the intensive
inntenssivve care
care
are unit
unit if
if they
the
hey had
had previously
previo
pre
eviouusly
ly received
reccei
eivved
experienced
bleed
shorter
stays
da
abi
b ga
gatr
tran
n ((mean
m an

me
n 11.6
.6 nnights)
ight
h s)) com
o pa
om
pare
r d with
with
h tthose
hos
osee wh
whoo ha
hadd rreceived
ece
ceiv
ived
ed
dw
arrfa
fari
r n (m
ri
(mea
eann 22.7
ea
.7 ni
nig
ghts;

t s;
dabigatran
compared
warfarin
(mean
nights;
pp=
0.01
0.
01).
)
).
p=0.01).
Co
Conc
nclu
lusi
sion
onssP
Pa
P ti
tien
ents
ts w
who
h eexperienced
ho
xper
xp
erie

ienc
nced
ed
dm
major
ajor
aj
or bbleeding
leed
le
ed
ding oon
n da
dabi
dabigatran
biga
gatr
tran
an rrequired
equi
eq
uire
redd mo
more
re rred
ed ccell
elll
el
ConclusionsPatients
transfusions but received less plasma, required a shorter stay in intensive care and had a trend to

lower mortality compared with those who had major bleeding on warfarin.
Clinical Trial Registration Information—ClinicalTrials.gov. Identifiers: NCT00262600,
NCT00291330, NCT00680186, NCT00329238 and NCT00558259.

Key words: hemorrhage, mortality, anticoagulants, atrial fibrillation, venous thrombosis

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DOI: 10.1161/CIRCULATIONAHA.113.002332

The oral thrombin inhibitor dabigatran etexilate (hereafter referred to as dabigatran) has been
approved in more than 80 countries for stroke prevention in atrial fibrillation based on the
superior stroke reduction with dabigatran 150 mg twice daily and non-inferior stroke prevention
with dabigatran 110 mg twice daily as compared with well managed warfarin (target INR 2-3;
median time in therapeutic range =67.3%) in the RELY trial.1 Major bleeding occurred with a
similar incidence in patients treated with dabigatran 150 mg twice daily compared with warfarin
but was less frequent in patients treated with dabigatran 110 mg twice daily. A lower rate of
bleeding was also seen with dabigatran 150 mg twice daily compared with warfarin (INR, 2.03.0) in patients with venous thromboembolism.2 In a pooled analysis of three trials of primary
prevention of venous thromboembolic events (VTE) in patients after total hip orr tota
ttotal
ota
tal kn
knee
ee
replacement,
eplacement, the risk of major bleeding was similar with dabigatran 150 mg and 220 mg once
daily
da

ailly compared
comp
co
mpar
mp
a ed with
ar
with
ith the low-molecular-weight heparin,
heparin, enoxaparin.
hep
enoxapaari
rin.3
Most vvitamin
itam
it
amin
am
n K antagonists
ant
ntag
ag
gonis
onists
t have
ts
have a long
lo
ong half-life
hal

alff-life
fe (acenocoumarol
(accenoccouuma
marroll 100 h;
h; warfarin
waarffar
a in
i 36-48
36-48
6-48 h;
phenprocoumon
120-150
reversed
within
minutes
ph
hen
e pr
proc
ocou
ouumo
monn 12
200-15
1500 h)
h but
but their
the
heiir
ir anticoagulant
anttic

icooagu
oagu
gula
lannt
nt eeffects
ffeccts ccan
ff
an bbee re
reve
verrseed
ve
ed w
itthi
h n 10-2
110-20
0 20 mi
minu
nute
t s
te
by prothromb
prothrombin
mbin
in ccomplex
ompl
om
plex
pl
ex
x cconcentrates

once
on
c nt
ce
ntra
r te
ra
tes (P
(PCC
(PCCs)
CCs)
CC
s)) aand
n w
nd
within
ithi
it
hiin 666-12
12 h bby
y vi
vita
vitamin
taami
minn K.
K4D
Dabigatran
abig
ab
i atran doess

ig
not have an antidote but has a half-life of 12-14 h5 and withholding the drug for 1-2 days is
sufficient to restore hemostasis in most cases of mild to moderate bleeding. In patients with lifethreatening bleeding, more rapid restoration of hemostasis might be achieved by the use of
hemodialysis to remove the drug,6-8 activated charcoal to prevent gastrointestinal absorption of
recently ingested drug,9 and the administration of PCCs,10activated PCCs11 or recombinant
activated factor VII (rFVIIa)12 to enhance thrombin generation. Evidence concerning the efficacy
of these approaches is, however, limited to experimental and animal studies and isolated case
reports.10, 13 Shortening of coagulation time is not always equivalent with restoration of

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DOI: 10.1161/CIRCULATIONAHA.113.002332

hemostasis. A monoclonal antibody that selectively and rapidly neutralizes dabigatran has been
developed but results from clinical trials are not yet available.14 In the absence of an effective
antidote, many clinicians are concerned that dabigatran-treated patients who experience major
cannot be adequately managed.15-17
The objective of this study was to describe the management of major bleeding and
outcomes after bleeding in large phase III trials evaluating the efficacy and safety of long-term
(at least 6 months) dabigatran compared with warfarin.

Methods
The Research Ethics Board of McMaster Faculty of Health Sciences – Hamiltonn Health
Heal
He
alth
th Sciences
Sci

cien
e ce
en
c s
approved the project without the need for patient consent. The data that were used for these
an
analyses
nal
alys
ysees
ys
es ddid
id nnot
ott ccontain
on
ontain
any personal identifiers
identifiers.
s.
The study
sttud
dy is
is based
based
ed on
on pooled
poolled
pool
d data
datta from

frrom
m trial
triiall populations
poopula
pulaati
t ons
ons with
with
wi
th aatrial
trria
iall fibrillation
fib
ibri
rill
lllat
a io
ionn (RE-LY
(R
RE-LY
E-LY
trial
riaal1) or
o vvenous
enou
en
ouss th
thromboembolism
hro
rom

mboemb
mboe
mb
bollis
ism
m (RE-COVER,
(RE(R
E-CO
ECOVE
CO
VE
ER,2 R
RE-COVER
E-CO
COVE
CO
VER
VE
R II
II,,188 R
RE-MEDY,
E--ME
EDY
DY,,199 aand
ndd R
REErial
ri
als)
al
s) (Table

(Ta
Tabl
ble 1).
bl
1) Patient
Pati
Pa
tien
ti
e t data
en
daata
t from
froom these
thes
th
esee trials
es
triaals
tr
l w
were
eree me
er
merg
merged
rged
rg
ed iinto
ntoo a co

nt
comm
common
mmon
mm
o dataset.
SONATE19 ttrials)
The comparator in all studies was warfarin, with the exception of RE-SONATE which compared
dabigatran with placebo. Patients in the placebo group in RE-SONATE did not experience any
major bleeding and were not included. Cases eligible for our analysis experienced centrally
adjudicated major bleeding on treatment or within 3 days of temporary or permanent
discontinuation of treatment. The purpose of this 3-day rule was to ensure that active drug was
likely to be in the circulation at the time of onset of bleeding. Major bleeding was defined
according to the ISTH criteria20 in all five trials. The protocols for the trials only recommended
general supportive measures in case of major bleeding on dabigatran. For non-responsive

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DOI: 10.1161/CIRCULATIONAHA.113.002332

patients with a life-threatening bleed the protocols listed fresh frozen plasma, activated
prothrombin complex concentrate or recombinant factor VIIa as options to be considered at the
discretion of the treating physician.
We calculated creatinine clearance with the Cockroft-Gault formula21 using the creatinine
level on admission or, if this was unavailable, the most recent creatinine level prior to the
bleeding event.
For the data extraction we used study databases and the bleeding and serious adverse
event narratives. Event narratives were obtained from Boehringer Ingelheim (Ridgefield, CT,

United States). A computer algorithm had been used to automatically generate major bleeding
event narratives whereas a medical writer had prepared narratives for life threate
ening
nin bbleeding.
leed
le
edin
ed
ing.
in
g
threatening
nvestigators at each site had prepared
d the serious adverse event narratives.
Investigators
As
Asse
sess
se
ssme
ss
ment
me
nt of
of resources
ressources
re
so
ma
ana

n gement
Assessment
used for bleeding management
D
Data
atta
ta on resour
resource
urce
cee uuse
see aand
nd
d tthe
he sshort-term
hort
ho
rt-t
rt
-tter
erm
m con
consequences
nseequeencess of
of m
major
ajjor bbleeding
leed
din
ingg in tthe
he R

he
RE-LY
E-LY
ELY ttrial
rial
ri
all w
were
ere
obtained
the
Population
Health
Research
(Hamilton,
Canada).
Using
RE-LY
ob
bta
tain
ined
in
e from
ed
fro
rom
m th
he Po
P

pulati
pul
lationn H
ealt
ea
lthh Rese
lt
R
ese
sear
arch
ar
h In
IInstitute
stiitutte (H
(Ham
amil
am
ilto
il
to
on, C
an
nada)
ada)). Usin
U
sin
ng tthe
hee RE-L
R

E-L
LY
trial
rial dataset ba
base
asee w
wee re
retrieved
etrrieve
vedd da
ve
data
ta oon
n th
thee nu
numb
number
mber
mb
err ooff un
unit
units
itss of bblood
it
lood
lo
od pproducts
rodu
ro
duct

du
ctss gi
ct
give
given
venn an
ve
andd
proportion of major bleeds treated with the different products; the proportion of events requiring
hospitalization, the length of stay in intensive care and in step-down unit, the decrease in
hemoglobin from baseline to the first hemoglobin level recorded during the event and from then
to the lowest level during the event, and the proportion of patients with associated
discontinuation of study medication or of aspirin. For the venous thromboembolism trials we
obtained data on blood product utilization from the event narratives (verified against the
databases from the sponsor).
Assessment of outcome of bleeding

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DOI: 10.1161/CIRCULATIONAHA.113.002332

Two of the authors (A M and H-G H) reviewed independently all narratives and extracted data
on patient characteristics, concomitant medication with aspirin or clopidogrel, type of bleeding,
treatments given for the bleeding, length of stay in the hospital and death after the bleeding. Data
from the narratives on deaths were verified against the individual study databases at Boehringer
Ingelheim.
It was not possible to blind the reviewers to the anticoagulant treatment because this
information was contained in the narratives.

For AF patients with intracranial hemorrhage, data on the modified Rankin Scale on
presentation and during follow up were obtained from the RE-LY database as a measure of
disability caused by the bleeding. Information on discharge destination after hosp
sppittal
a izzatio
atio
ionn fo
ffor
or
hospitalization
he bleeding event was also collected from this database as an indirect indicator of the overall
the
di
isaabi
bili
litty.
li
ty
disability.
Stat
S
tattis
i tical an
nal
alyysees
Statistical
analyses
Th
he analyses
anal

an
alys
yses
ys
es of
of resource
reso
reso
s ur
urce
cee utilization
utili
liza
li
zaati
tion
on were
were
ere ba
base
ed onn aall
lll m
ajoor
aj
or bbleeding
l edin
le
edin
ingg even
eevents,

ven
e ts
ts,, wh
w
ereas th
ere
thee
The
based
major
whereas
analyses of outcomes
ouutc
tcom
om
mes
e after
aft
f err a major
maj
ajor
o bleed
or
ble
leed
ed were
wer
eree based
base
ba

seed onn the
the first
firrst event
eve
vent
nt per
per patient.
pat
atie
ient
ie
nt.. Co
nt
Comparisons
between dabigatran 110 mg and 150 mg twice daily as well as between the combined dabigatran
groups and warfarin were performed with chi square test or Fisher’s exact test for categorical
data and Student t-test or non-parametric Wilcoxon test for continuous variables. Cumulative
risk for death was estimated with Kaplan-Meier analysis. Odds ratio (OR) for mortality 30 days
after the bleeding event was calculated by logistic function regression to adjust for sex, age,
weight, renal function and additional antithrombotic therapy, using SAS Proc logistic (SAS
version 9.2, Cary, NC) and reporting Wald chi-square p-values and confidence intervals.
Sensitivity analyses were performed for the main outcomes (7- and 30-day mortality,

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DOI: 10.1161/CIRCULATIONAHA.113.002332

transfusions of blood or plasma, vitamin K administration, and nights in intensive care setting)

with major bleeding occurring on active treatment. Furthermore, we analyzed when appropriate
with correction for multiple events using the generalized estimating equation (GEE) for
estimation of the parameters of a generalized linear model with a possible unknown correlation
between outcomes.

Results
Baseline characteristics
The number of patients randomized in the five studies, the number of major bleeding events,
patients with bleeding, narratives reviewed
d and event rates are summarized in Ta
ablle 11.. In
n tthe
he
Table
RE-LY trial patients were randomized 2:1 to dabigatran
a
vs. warfarin. In total, 1,121 major
bl
leeedi
dinng
ng eevents
v nts oc
ve
occu
curred in 1,034 patients for wh
whom
om
m we reviewed
d thee nnarratives,
ar

arratives,
usually
bleeding
occurred
co
onsisting
ns
of an eevent
vent
nt na
arra
arra
rati
tive
ti
ve aand
nd a se
ser
riou
us aadverse
dveerse ev
even
entt narr
nnarrative.
arrat
ativ
ive.
e
consisting
narrative

serious
event
Ch
Char
araacte
ar
acterrisstic
sticss of
of the
the patients,
pat
atie
ient
ie
nts,
nt
s, for
for whom
who
om the
thee narratives
nar
a ra
rati
tive
ti
vees were
were reviewed,
revi
evieweed, and

and ttheir
heiir
he
Characteristics
concomitantt an
anti
t th
ti
hro
romb
mbot
mb
o ic medications
med
dic
icat
atio
at
i ns aare
ree sshown
hown
ho
wn iin
n Ta
Tabl
blee 22.. Th
bl
T
oca
cati

tion
ti
on ooff bl
blee
eedi
ee
d ng events iis
di
antithrombotic
Table
Thee lo
location
bleeding
shown in Table 1 in the Supplemental material. The discrepancy between the 1,034 narrated
events and the 1,507 bleeds reported from the studies is due to our stricter cut-off for the interval
between last dose and onset of bleeding.
There were no statistically significant differences between the characteristics of the
patient population with major bleeding in the narratives from all phase III trials and the 1,162
patients with major bleeding previously reported from the RE-LY trial1 (not shown). Patients
with major bleeding during treatment with dabigatran were significantly older (75.3 years) and
had lower creatinine clearance (median 53 mL/min) than those with major bleeding during

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DOI: 10.1161/CIRCULATIONAHA.113.002332

treatment with warfarin (71.8 years; 62 mL/min). Furthermore, a larger proportion of the patients
treated with dabigatran who experienced bleeding had received concomitant treatment with

aspirin (30.9%) or a non-steroid anti-inflammatory agent (12.9%) than those treated with
warfarin (24.6% and 8.4%, respectively).
Resources and management strategies used for major bleeding
Blood transfusions and drop in hemoglobin
For 365 (33%) major bleeding events in the 5 trials no blood products or other hemostatic agents
were given (dabigatran 110 mg – 100 of 293 events [34%], dabigatran 150 mg – 126 of 403
events [31%], warfarin – 139 of 425 events [33%]). The difference was not significant for any
comparison between the three groups. Red blood cell transfusion alone, i.e. witho
hooutt any
ny oother
ther
th
e
er
without
blood products, coagulation factors, vitamin K or local hemostatic intervention, was given more
of
fteen in ddabigatran
abig
ab
igatra
ig
raan tr
ttreated
eated patients, for 395 blee
edin
ding events (35%)
(35%
%) (dabigatran
(dab

ab
big
igatran 110 mg – 137 of
often
bleeding
2293
93 bl
bbleeds
eeds [47
7%], da
dab
bigatr
gatr
tran
an
n 1150
50
0m
g – 1733 ooff 40
03 ble
eed
ds [4
[[43%],
3%]], w
3%
arfa
ar
f rinn – 85
85 ooff 42
4255 bl

blee
eeds
ds
[47%],
dabigatran
mg
403
bleeds
warfarin
bleeds
20%
0%])
]);; the
])
the differences
diff
di
ffeereence
encees are
a e significant
ar
siign
gnif
ific
if
icaant
ic
ant for
fo
or all

al comparisons
com
co
mpaarisson
ns of dabigatran
dab
big
gat
atra
raan vs.
vs warfarin
warf
wa
rfar
arin
ar
in with
witth a
[20%]);
imilar patter
ernn in
i tthe
he R
E LY sstudy
Etu
udy aalone
lone
lo
n ((Table
ne

Tabl
Ta
blee 33).
bl
) T
).
hee m
edia
ed
iann nu
ia
umb
mber
er ooff re
redd ce
cell
ll uunits
n ts
ni
similar
pattern
RE-LY
The
median
number
transfused per patient did not differ between the groups.
In the RE-LY database the decrease in hemoglobin from baseline to the time of bleeding
was greater in patients randomized to receive dabigatran compared with warfarin (dabigatran,
38.0 g/L, warfarin, 30.7 g/L; p=0.02). A decrease in hemoglobin from baseline was also noticed
for patients in the dabigatran and warfarin treatment arms that did not have any bleeding event.

For the dabigatran 110 mg group, the mean reduction in hemoglobin at 12 months was 0.6 g/L
greater (95% confidence interval [CI]: 0.14–1.06) than that for warfarin (p=0.011). For the
dabigatran 150 mg group, the corresponding figures were 1.1 g/L (95% CI: 0.63-1.57)

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(p<0.0001).
Hemostatic treatment
Only a minority of the patients received any hemostatic therapy, i.e. plasma, vitamin K, factor
concentrates, cryoprecipitate or platelets. In patients with major bleeding events in the RE-LY
database, there was significantly less use of fresh frozen plasma or vitamin K for the dabigatran
groups compared to the warfarin group (Table 3). The proportion of patients receiving plasma or
vitamin K was similar in the venous thromboembolism studies to those in RE-LY. The
utilization of cryoprecipitate, platelets, PCC, rFVIIa or other coagulation factors was low overall
and did not differ significantly between the dabigatran- and warfarin-groups.
In all 5 trials vitamin K was given as the only treatment to patients on wa
arf
rfar
arin
ar
n ffor
or 559
9
warfarin
bleeds (14%) and as an adjunct for another 73 bleeds (17%) and less often to patients on
da

abi
biga
gatr
ga
tran
tr
an
n 110mg
110mg
mg or
or 150 mg, for 18 (2.6%) andd 39
3 bleeds (5.6%),
(5.6%)
%)), resp
sppec
ectively. Any local or
dabigatran
respectively.
nvaasi
s ve proce
edu
duree to
to st
stop
op tthe
he bl
blee
eeedin
ding w
as uused

sed in
n 9%
% of bbleeds
leed
ds in ppatients
atieent
ntss on
on ddabigatran
abig
ab
igaatra
ig
raan 11
1110
0
invasive
procedure
bleeding
was
mg
g, 12%
12% of bleeds
ble
leeeds on dabigatran
dab
a ig
igat
a raan 150
at
150 mg,

mg, and
and 14%
1 % off bleeds
14
ble
leeeds
eds on
o warfarin
warf
r arin
ar n ((significant
sign
si
gnif
gn
ific
iccant
an ddifference
ifffer
ffereence
ence
c
mg,
between dabi
biga
gatr
ga
t an 1110
tr
10 m

g aand
ndd w
arfa
ar
f ri
rin;
n; pp=0.013).
=0
0.0013
13).
).
dabigatran
mg
warfarin;
Hemodialysis for drug removal was used in a single case on dabigatran. In this patient,
after 6 hours of dialysis, prior to which massive transfusions with blood, plasma, platelets,
cryoprecipitate, 5 doses of rFVIIa and fibrin glue had been ineffective, the thrombin time
shortened from 128 s to 65 s and bleeding ceased. The effect of hemodialysis was assessed as
good.7
Hospital resources
Based on RE-LY data, the length of stay in intensive care units was shorter for the dabigatran
patients (1.6 nights, mean) than for the warfarin patients (2.7 nights; p=0.01). There was,

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according to the narrative assessments, numerically fewer surgical interventions for the

dabigatran patients (12.1%) versus the warfarin patients (15.0%; p=0.17) to stop the bleeding
(Table 4).
Outcomes after major bleeding
Mortality
The crude mortality in the 5 studies at 7 and 30 days after the onset of the first major bleeding
event among the dabigatran- and the warfarin-patients was 5.3% vs. 8.4% (p=0.045) and 9.1%
vs. 13.0% (p=0.057), respectively. The Kaplan-Meier analysis indicated a trend to reduced risk
for death with dabigatran (110 mg and 150 mg combined) versus warfarin during 30 days from
he bleeding, p=0.052 (Figure 1). Adjusted for sex, age, weight, renal function aatt th
he ti
time
me ooff th
the
the
the
bleed and additional antithrombotic therapy the OR for 30-day mortality in the combined
da
abi
biga
gatr
ga
tran
tr
an
n treatment
treeatme
mennt groups was 0.66 (95% CI: 0.44-1.00;
me
0.44-1.00; p=0.051).
0.4

p=0.051
5 ). The
The corresponding adjusted
dabigatran
ORs
O
Rs separately
ly ffor
orr dabigatran
dab
a ig
gat
atra
rann 110
ra
110 mg
mg oorr da
abi
bigatrran
n 150
50 m
g ve
vers
rsuus w
arffari
farinn were
weree 00.65
.655 (9
.6
95% C

I:
dabigatran
mg
versus
warfarin
(95%
CI:
0.
.38
38-1
-1
1.1
. 1)) and
and
nd 0.68
0.68
68 (95%
(9
95%
% CI:
I: 0.42-1.08),
0.42422-11.0
08),
08),
) respectively.
res
espe
pect
pe
ctiiveely.

y. For
For the
the R
E--LY po
opul
opul
ulat
atio
at
i n alon
io
aalone,
l ne,, tthe
hee
0.38-1.11)
RE-LY
population
adjusted OR
R fo
forr 30
0-d
day
a mor
orta
or
taliity ffor
ta
or ddabigatran
a ig
ab

igat
a ra
at
rann ttreatment
reeat
a meent ggroups
roup
ro
upss co
up
comb
mbin
mb
in
ned w
as 00.56
.566 (95% CI:
.5
30-day
mortality
combined
was
0.36-0.86; P=0.009), for dabigatran 150 mg was 0.52 (95% CI: 0.31-0.88) and for dabigatran 110
mg was 0.60 (0.35-1.03). For patients with venous thromboembolism there was no reduction of
mortality in the dabigatran group but the number of events was small. The main difference in
cause of death after major bleeding between the patients with atrial fibrillation and venous
thromboembolism appeared to be concomitant cancer (5% vs. 36%; p=0.003).
Disability
Data on the initial and final modified Rankin Scale evaluations were recorded for 78 (55%) of all
patients with intracranial hemorrhage. There was no statistically significant difference between

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dabigatran and warfarin or between the two doses of dabigatran for any comparison of the
change in score (Table 4).
For 710 (52%) of the bleeding events requiring hospitalization in the RE-LY trial, the
discharge destination was specified as one of three categories (home, long term facility, or other
hospital). There was no significant difference in the proportion of these destinations according to
treatment (Table 4).
Sensitivity analyses
Results for transfusion of blood or plasma, or for administration vitamin K and for drop in
hemoglobin from baseline until admission for bleeding, and for nights in intensive care were
imilar to the above reported, when analyzed only for events on treatment (Table
le 2 in
in the
th
he
similar
Supplemental material). The all-cause mortality for bleeding events restrictedd to the on treatment
pe
eriiod only
onl
nlyy in the
hee 5 trials was 4.8% in the dabigatran
dabiga
gaatraan group and 7.7%

7.7
. % in tthe
he warfarin group
period
p=00.062) at 7 ddays
ays an
ay
nd 88.1%
.1%
1% aand
ndd 112.6%,
2.6%
6%, re
esppectiively
y, at
at 330
0 da
day
ys ((p=0.018).
p=00.018)
p=
8). Th
8)
Thee ad
dju
just
s ed oodds
ddds
(p=0.062)
and

respectively,
days
adjusted
ati
tioo for
for 30-day
300-d
-day
ay mortality
mor
o taality
ty in
in the
t e dabigatran
th
dabi
da
b gaatrran group
bi
g ou
gr
oupp and
an
nd bleeds
bllee
eedds on
on treatment
trea
tr
eatm

ea
tm
men
nt was
was 0.
0.62
62 ((95%
955% CI
I:
ratio
CI:
0.40-0.96; pp=0.03).
=0
0.0
03)
3)..
Hemostatic treatment for all major bleeding events, analyzed with correction for multiple
events with the GEE method (Table 3 in Supplemental material) showed similar results as in the
main Table 3.

Discussion
It has previously been reported that the risk of intracranial bleeding (RE-LY) or clinically
relevant bleeding (RE-LY, RE-COVER) is lower with dabigatran than with warfarin.1, 2 We are
now presenting data on the management and outcome of major bleeding events in 5 phase III

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trials on long-term treatment with dabigatran. One of the most important findings of our study is
that patients who had a major bleeding event on dabigatran treatment were older, had worse renal
function and more often concomitant treatment with aspirin or a non-steroid anti-inflammatory
agent than those with warfarin. This implies that when bleeding occurs with dabigatran, the
patient is usually at higher risk compared to patients with major bleeding events on warfarin and
raises the possibility that some of these bleeds might be avoidable by using a lower dose of
dabigatran, as also recommended in some treatment guidelines.22 Avoidance of concomitant
medication with aspirin and non-steroid anti-inflammatory agents might also reduce the risk and
severity of bleeding.
Most major bleeding events were managed with supportive care only. Coagulation
Cooagul
agu atio
atio
ionn factor
fact
fa
ctor
concentrates were rarely used, irrespective off the anticoagulant therapy. Patients with bleeding
onn dabigatran
dab
abig
igat
ig
atra
at
r n were
ra
weere more often transfused with red
red cells

cells while patients
paati
tients
ts w
i h bleeding on warfarin
it
with
m
orre
re often received
recceiive
ved plasma.
p assma
pl
ma.. This
T is was
Th
was primarily
primaariily explained
expplaiined by greater
gre
reaater
ater use
usee of
of red
reed cell
ceelll ttransfusion
raanssfusi
fus on
more

n dabigatran
dab
abig
igat
ig
atra
rann co
ra
comp
mpar
mp
areed
ed w
i h wa
it
arf
rfar
arin
ar
in --treated
trrea
eatted
ted ppatients
attieent
n s wh
whoo ex
expe
peeriien
ence
ceed ma

ajo
jorr ga
gast
strroin
st
in
nteest
stin
in
nall
in
compared
with
warfarin
experienced
major
gastrointestinal
bleeding (71%
% vs
vvs.. 54
54%
% tr
ttransfused,
ansf
an
sfus
sf
ussed
ed, re
rrespectively).

sppec
ecti
tive
ti
vely
ve
ly)). Th
ly
Thee ou
utc
tcom
omee of
om
o m
ajoor bl
aj
blee
e di
ee
ding
ng eevents
vent
ve
n s in
outcome
major
bleeding
patients on dabigatran was better than in those on warfarin, as evidenced by a shorter stay in the
intensive care unit and a trend towards lower adjusted all-cause mortality at 30 days after major
bleeding.

The 1,121 major bleeding events assessed by our two independent reviewers is lower
than the total of 1,507 events reported from the 5 studies, because we had a strict cut-off of 3
days after the last dose of study drug. Thus we only included events that had a probable temporal
relationship to the study drug. In a few cases the use of a blood component or plasma derivative
was detected by narrative analysis, which had not been entered into the case report form

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(=database) and vice versa.
In the five trials with a pooled population of 27,419 patients the prevalence of risk factors
for bleeding was balanced at baseline but not subsequently at the time of major bleeding for
those with an event. RE-LY trial analyses have demonstrated that both age and renal function are
independent risk factors for bleeding and there was also an interaction between age and
randomized treatment for major extracranial bleeding. There was no interaction between renal
function as assessed by the Cockgroft-Gault formula and treatment, which is a surprising finding
because renal function is a determinant of dabigatran exposure.23 Other analyses have not
consistently shown that renal dysfunction is a risk factor for bleeding in patients treated with
anticoagulants,23, 24 although low-molecular-weight heparin, which like dabigatr
dabigatran
ran depends
dep
pen
ends
ds on
on
renal

enal elimination, is associated with a higher incidence of bleeding at low glomerular filtration
rates.
atees.
s.25 Concomitant
Con
onco
co
omiita
tannt antiplatelet therapy has been
en sshown
hown to incre
increase
eas
a e th
the
he rrisk
isk of bleeding in
patients
pati
ien
e ts on wa
warfarin
arffariin aand
nd
d ddabigatran.
abig
ab
igat
ig
atra

raan..26, 277 The
hee higher
highherr pr
prevalence
rev
val
alen
ence
en
ce ooff these
thes
th
ese risk
risk
skk factors
fac
acto
to
ors in
in patients
paatien
tien
ntss
treated
reaateed with
with
h ddabigatran
abiigaatra
ab
atrann compared

c mp
co
par
ared
ed
d with
wit
ithh warfarin
warf
wa
rfar
rf
arin
in w
who
ho eexperienced
xpper
eriienc
nceed ma
nc
majo
major
jo
or bl
bbleeding
eeedi
ding
ng ssuggests
ugges
ugg

gests
sts th
that
hatt
dabigatran iss as
asso
associated
s ci
so
ciat
a ed w
at
with
ithh a hi
it
high
higher
gher
gh
e tthreshold
er
h es
hr
e ho
hold
ld ffor
or bbleeding.
l ed
le
edin

in
ng.
The greater reduction in hemoglobin in the dabigatran group from baseline to the time of
admission for the bleed is most likely explained by the higher incidence of gastrointestinal
bleeding and lower incidence of intracranial bleeding with dabigatran. It is, however, reassuring,
that there was no difference between the treatments for the additional reduction of hemoglobin
until the lowest level recorded. The drop in hemoglobin seen in patients treated with warfarin or
dabigatran, who did not experience any bleeding event might be related to occult gastrointestinal blood loss. Even though the decrease in hemoglobin was greater in the dabigatran
groups than in the warfarin group, the mean difference between the two anticoagulants was

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modest (1.1 g/L per 12 months for the dabigatran 150 mg group).
Dialysis to eliminate dabigatran was only employed in a single case, refractory to
treatment with a variety of blood products, and the response was recorded in the narrative as
good.7 This is supported by experimental data and some clinical data.6, 8 There was not sufficient
data to identify any coagulation factor product that would be useful to reverse the effect of
dabigatran. Perhaps surprisingly, of 418 bleeds on warfarin only 12 were managed with rapidly
acting reversal agents (n=10 with PCC, n=2 with rFVIIa). This probably reflects clinical
practice, since major bleeds were at least initially managed by staff in the emergency
department; not necessarily at the site of the investigator but at the nearest hospital. The median
amount of plasma transfused (4 units) is about halff of what has been calculated aass ne
nnecessary
ceessar
sssar
aryy to

normalize the prothrombin time.28
T
hiss analysis
hi
anal
allys
ysis
is presents all-cause mortalityy within
wi
aft
f err a major
major bleed as opposed
This
30 days after
to
o the
thhe
he data from
om RE-LY
REE-LY
L ppublished
LY
ubli
ub
bli
lish
shed
ed
d bby
y Ei

Eik
Eikelboom
kelb
boom ett al,, sshowing
howi
ho
wing
wi
ng ffatal
atal bbleeding,
leed
le
edin
in
ng,
g, ii.e.
.ee. bl
bbleeding
eeediing
leading
ead
adin
in
ng to death,
dea
eath
th,, without
withou
with
ou

ut a specified
sppeccif
ifie
iedd ti
ie
time
me fframe.
rame
ra
me..2233 IInn a recent
me
rece
re
cent
ce
ntt analysis
analy
naly
ysi
s s off intracranial
intr
in
trac
tr
accra
rani
niaal
ni
hemorrhagess in RE-LY,
REE LY

LY,, mortality
mort
mo
rtal
rt
alit
ityy after
it
afte
af
t r intracranial
in
ntr
trac
acra
ac
rani
ra
niial hhemorrhage
em
mor
orrh
rhag
rh
agee wa
ag
wass si
simi
mila
mi

larr fo
la
or da
dabi
biga
bi
g tran and
similar
for
dabigatran
warfarin, whereas the number of fatal intracranial bleeds was higher in the warfarin arm than in
either of the dabigatran arms.29 Warfarin treatment increases the risk of hematoma expansion in
patients with warfarin related intracranial hemorrhage.30 Early reversal of the anticoagulant
effect of warfarin seems to limit hematoma expansion,31, 32 the size of which is related to the
functional outcome and mortality after ICH.30, 33 It appears that management of warfarinassociated bleeding is suboptimal,32 probably requiring more education and implementation of
guidelines that have been developed to support the use of PCC for rapid reversal.4 Vitamin K
was only given to 31% of patients with warfarin treatment at the time of a major bleed without

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any preference to a particular type of bleed. Appropriate use of these reversal agents could have
improved the outcomes for the warfarin patients.
A strength of this study is that we have used all the data available in the RE-LY database
and in addition the serious adverse event- and major bleeding narratives from all 5 trials to assess
the treatment of bleeding. One of the limitations is that the treatment with dabigatran versus
warfarin in the RE-LY trial was open, although the data reported on use of blood products,

length of stay, and mortality is unlikely to be biased. Another limitation is that management of
bleeding was not determined by random allocation. We also acknowledge that our study is a
retrospective analysis, with the potential for biased data acquisition and outcome ascertainment.
However, all data for these analyses were collected prospectively in the 5 clinical
all ttrials,
r alls, uusing
ri
sing
si
n
ng
detailed and specific data acquisition forms, and all major bleeding events were classified as
uch
h bby
y an
n iindependent
n ep
nd
pen
ende
d nt adjudication committee. F
inally, the dataa pr
ppresented
essen
entted
te have been derived
such
Finally,
ffrom
rom

m clinical tr
tria
ialss w
ia
ith se
it
sele
lect
le
cteed
ct
ed ppatients
attie
iennts
nts and
ndd tthe
he rresources
esouurcces re
equiireed orr the
equi
thhe
he outcomes
outtco
com
mes of major
mes
maj
ajoor
trials
with

selected
required
bl
lee
eedi
ding
di
ng might
mig
ight
ht be
be different
diff
di
ffferrent
ren in
in real
reeal world.
worrld
d.
bleeding
In conclusion,
con
on
ncl
clus
usio
us
ion,
io

n the
n,
the
h overall
ove
vera
raall resources
ressour
urce
cees required
requ
re
quir
qu
irred to
to manage
mana
ma
nage
na
ge bleeding
ble
leeedi
ding
ng were
wer
e e not
not greater
grea
gr

e ter and thee
ea
prognosis after a major bleeding was not worse than after a warfarin-associated bleed. More
frequent transfusion with red cells was counterbalanced by shorter stay by approximately one
day in the intensive care unit and less frequent transfusion of plasma. Our results point at the
need for protocols to evaluate coagulation factor concentrates for the management of dabigatranassociated bleeding and for improved knowledge translation to manage warfarin-associated
bleeding.
The main clinical implication of this study is that dabigatran offers an alternative to
warfarin with similar or superior efficacy, carrying similar or lower risk for major bleeding

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events (especially intracranial hemorrhage), that can be managed satisfactorily with simple
measures (drug discontinuation, transfusion of red cell concentrates) with a trend to lower
mortality after such bleeding events compared to warfarin. The overall safety profile of
dabigatran is favorable. Whether the management of bleeding on dabigatran can be further
improved by a specific antidote remains to be evaluated.14

Funding Sources: This study was funded by a grant from Boehringer Ingelheim

Conflict of Interest Disclosures: Dr. Majeed and Dr. Hwang report no conflicts. Dr Connolly,
grant support/ honoraria/ consulting fees from Boehringer-Ingelheim, Bristol-Myers Squibb,
Sanofi-Aventis, and Portola; Dr Eikelboom, honoraria and research support from
m Ba
Baye
yerr,

ye
r,
Bayer,
Boehringer Ingelheim, Bristol Myers Squibb, JnJ and Pfizer; Dr. Ezekowitz, con
consulting
nsuult
ltiing
ing fees,
fees
fe
es,
es
ecture fees, and grant support from Boehringer Ingelheim, Bristol Myers Squibb and Aryx
lecture
Th
her
erap
apeu
ap
euti
tics
ti
c , consulting
cs
co
ons
nsul
u ting fees from Sanofi- Aventis,
Avennti
t s, and lecture ffees

e s an
ee
nd gr
ggrant
ant support from
Therapeutics,
and
Po tola Pharmaceuticals;
Port
Phar
arma
maaceu
ceutic
iccal
als;
s; Dr
Dr Wallentin,
Wall
Wa
llen
ll
en
ntiin, grant
graant support/
supp
su
port/ honoraria/
hon
onor
orar

or
a ia
ar
ia// co
cons
nsuult
ns
ulting
ti g ffees
eess fr
ee
from
om
Portola
consulting
B
oeehringer
eh
Ing
n ellheim
m, Regado
Rega
gaadoo Biosciences,
Bio
osc
s iences,, Athera
Atheeraa Biosciences,
Bio
iosc
scie

sc
ienncess, Astra-Zeneca,
ie
Astraa-Z
Zenec
Zen
neca,
ca,
Boehringer
Ingelheim,
Glax
Gl
ax
xoS
oSmi
mith
mi
thKl
th
Klin
in
ne,
e, Eli
Eli Lilly,
Lil
illy
ly, Schering-Plough,
Sche
Sc
heri

he
ring
ri
ng-P
-P
Plo
loug
ughh,
ug
h, and
and Bristol-Myers
Brissto
Bris
toll-My
lMyer
My
erss Squibb;
Squi
Sq
uibb
ui
bb;; Dr
bb
Dr Yusuf,
Yusu
Yu
suff,
su
f, grant
gra

rant
nt
GlaxoSmithKline,
upport/ honoraria/
hon
nor
orar
aria
ar
iaa/ co
cons
nsullti
ns
ting
ng ffees
eess fr
ee
ffrom
om
mB
oehr
oe
hriing
hr
n er IIngelheim;
nggel
elhe
heim
he
im;; Dr

im
Dr.. Sc
Schu
hulm
hu
lman
lm
an
n hhonoraria
onor
on
orar
or
a ia from
support/
consulting
Boehringer
Schulman
Boehringer Ingelheim, Bayer and Merck; Dr Brueckmann and Dr. Fraessdorf are full-time
employees of Boehringer Ingelheim.

References:
1. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA,
Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H,
Diener HC, Joyner CD, Wallentin L, the RE-LY Steering Committee and Investigators.
Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:11391151.
2. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee
J, Goldhaber SZ. Dabigatran versus warfarin in the treatment of acute venous thromboembolism.
N Engl J Med. 2009;361:2342-2352.

16
Downloaded from by guest on April 27, 2014


DOI: 10.1161/CIRCULATIONAHA.113.002332

3. Friedman RJ, Dahl OE, Rosencher N, Caprini JA, Kurth AA, Francis CW, Clemens A, Hantel
S, Schnee JM, Eriksson BI. Dabigatran versus enoxaparin for prevention of venous
thromboembolism after hip or knee arthroplasty: a pooled analysis of three trials. Thromb Res.
2010;126:175-182.
4. Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ, Svensson PJ, Veenstra
DL, Crowther M, Guyatt GH. Evidence-based management of anticoagulant therapy:
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e152S-184S.
5. Stangier J, Rathgen K, Stahle H, Gansser D, Roth W. The pharmacokinetics,
pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor,
in healthy male subjects. Br J Clin Pharmacol. 2007;64:292-303.
6. Stangier J, Rathgen K, Stahle H, Mazur D. Influence of renal impairment on the
pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallelgroup, single-centre study. Clin Pharmacokinet. 2010;49:259-268.
7. Warkentin TE, Margetts P, Connolly S, Lamy A, Ricci C. Recombinant factor
or V
I a (r
II
(rFV
FVII
FV
IIa)
II
a)
VIIa

(rFVIIa)
and hemodialysis to manage massive dabigatran-associated postcardiac surgery bbleeding.
leed
le
edin
ed
in
ng. Bl
Bloo
oodd.
Blood.
2012;119:2172-2174.
8.. Khadzhynov
Kha
hadz
dzhy
dz
hyno
hy
noov D,
D Wagner
Wagner F, Formella S, Wiegert
Wiege
geert E,
E, Moschetti V,
V, Slowinski
Sllow
owin
i ski T, Neumayer HH,
Li

iessenfeld
dK
H, L
H,
e r T, H
eh
a tt
ar
tter
err S
Frie
iedm
dman
an JJ,, Pe
Pete
terrs H,
H, Clemens
Clem
Cl
e en
ns A. Effective
Eff
ffeectiivee elimination
eli
limi
mina
nati
tion
ti
on of

of
Liesenfeld
KH,
Lehr
Hartter
S,, Fr
Friedman
Peters
ddabigatran
dab
abiga
g tran by haemodialysis.
haem
ha
mod
odia
ialy
lysi
ly
siss.
si
s. A phase
pha
hase
se I single-centre
singglee-cen
ntre study
study
stu
udy inn patients

patiient
ntss with
with end-stage
end-s
nd-sta
t ge
ta
ge renal
ren
nal
dise
di
eas
a e. Thromb
Thro
romb
mb Haemost.
Haemo
most. 2013;109:596-605.
mo
20113;1
; 09
9:5
596
6-6005.
0 5.
disease.
9. vvan
an R
yn JJ,, St

Stangi
gier
er J, Ha
H
ertt
er
tter
er S
sen
enfe
feld
ld K
H, W
iene
ie
nenn W
Feur
urin
ing M,
M C
leme
le
m ns A
Ryn
Stangier
Haertter
S,, Lies
Liesenfeld
KH,
Wienen

W,, Fe
Feuring
Clemens
A..
Dabigatran eetexilate--a
teexi
x laate
te---aa no
nnovel,
vel,
ve
l, rreversible,
eve
v rs
rsib
ible
le,, or
le
oral
al ddirect
irrec
ectt th
tthrombin
ro
omb
mbin
in inhibitor:
inh
nhib
bit

i or
or:: interpretation
inte
in
terp
te
rp
pre
reta
tati
ta
tiion of
coag
co
agul
ulat
atio
ionn assays
assa
as
says
ys and
and reversal
rev
ever
erssal of
of anticoagulant
anti
an
tico

coag
agul
ulan
antt activity.
acti
ac
tivi
vity
ty Thromb
Thro
Th
romb
mb Haemost.
Hae
aemo
most
st 2010;103:11162010
20
10;1
;103
03:1
:111
1166coagulation
1127.
10. Zhou W, Schwarting S, Illanes S, Liesz A, Middelhoff M, Zorn M, Bendszus M, Heiland S,
van Ryn J, Veltkamp R. Hemostatic therapy in experimental intracerebral hemorrhage associated
with the direct thrombin inhibitor dabigatran. Stroke. 2011;42:3594-3599.
11. Dager W, Roberts A. Reversing dabigatran with FEIBA in a patient with a transseptal
perforation during cardiac ablation. Crit Care Med. 2011;39 (Suppl):243.
12. van Ryn J, Kink-Eiband M, Clemens A. The successful reversal of dabigatran-induced

bleeding by coagulation factor concentrates in a rat tail bleeding model do not correlate with ex
vivo markers of anticoagulation. Proceedings of American Society of Hematology Conference,
San Diego. 2011:Abstract 2316..
13. Lillo-Le Louet A, Wolf M, Soufir L, Galbois A, Dumenil AS, Offenstadt G, Samama MM.
Life-threatening bleeding in four patients with an unusual excessive response to dabigatran:

17
Downloaded from by guest on April 27, 2014


DOI: 10.1161/CIRCULATIONAHA.113.002332

implications for emergency surgery and resuscitation. Thromb Haemost. 2012;108:583-585.
14. Schiele F, van Ryn J, Canada K, Newsome C, Sepulveda E, Park J, Nar H, Litzenburger T. A
specific antidote for dabigatran: functional and structural characterization. Blood.
2013;121:3554-3562.
15. Cotton BA, McCarthy JJ, Holcomb JB. Acutely injured patients on dabigatran. N Engl J
Med. 2011;365:2039-2040.
16. Harper P, Young L, Merriman E. Bleeding risk with dabigatran in the frail elderly. N Engl J
Med. 2012;366:864-866.
17. Radecki RP. Dabigatran: uncharted waters and potential harms. Ann Intern Med.
2012;157:66-68.
18. Schulman S, Kakkar AK, Schellong S, Goldhaber SZ, Eriksson H, Mismetti P, Christiansen
AV, Schnee J, Kearon C. A randomized trial of dabigatran versus warfarin in the treatment of
acute venous thromboembolism (RE-COVER II). Proceedings of American Society
Societ
etyy of
o
Hematology Conference, San Diego. 2011:Abstr 205.
19. Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM,

Friedman J, Mismetti P, Goldhaber S, for the RE-MEDY and the RE-SONATE
RE-SO
SONATE Trials
nveest
stig
igat
ig
ator
at
ors.
or
s. Ext
xteended
xt
en
use of dabigatran, warfa
arin
rin or placebo inn ve
vvenous
noous tthromboembolism.
hromboembolism. N
Investigators.
Extended
warfarin
En
ngl J Med
d. 2013;368:709-718.
2013
2013
3;3

; 68
68:7
:709
:7
09
9-7
-718
18..
Engl
Med.
20
0. Schulman
Schulman
an S, Kearon
Kearronn C.. Definition
Deefini
n ti
tion
o of
on
of major
maajo
or bleeding
blleedi
ding
ng in
in cclinical
liniicaal investigations
invvest
stig

gattio
ons off
20.
an
nti
tihe
hemo
he
m sttat
mo
atiic
ic medicinal
med
dic
iciina
inal
al products
pro
odu
duct
ctss in
ct
in non-surgical
nonnonn-su
surggic
su
i al
al patients.
pat
atie

i nt
ie
ntss.
s. J Th
T
r mb Haemost.
ro
Haemo
aemo
most
st.. 20
st
200
05;3
;3
3:6
692
92--6994.
94
antihemostatic
Thromb
2005;3:692-694.
21. Hellden A, O
darda
r Ce
rCede
derl
rlof
rl
of II,, Ni

N
lssoon G, S
ls
jov
o ik
iker
er S
Sode
ders
de
rsstr
trom
om A
Eule
lerr M, O
le
hlen
hl
e G,
en
Odar-Cederlof
Nilsson
Sjoviker
S,, So
Soderstrom
A,, Eu
Euler
Ohlen
Be
Berg

rgma
mann U.
U Renal
Ren
enal
al function
fun
unct
ctio
ionn es
esti
tima
mati
tion
onss and
and dose
dose recommendations
rec
ecom
omme
mend
ndat
atio
ions
ns for
for dabigatran,
dab
abig
igat
atra

rann ggabapentin
abap
ab
apen
enti
tinn
Bergman
estimations
and valaciclovir: a data simulation study focused on the elderly. BMJ Open. 2013;3.
22. Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, Al-Attar N,
Hindricks G, Prendergast B, Heidbuchel H, Alfieri O, Angelini A, Atar D, Colonna P, De
Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M, Hohloser SH, Kolh P, Le Heuzey JY,
Ponikowski P, Rutten FH. Guidelines for the management of atrial fibrillation: the Task Force
for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur
Heart J. 2010;31:2369-2429.
23. Eikelboom JW, Wallentin L, Connolly SJ, Ezekowitz M, Healey JS, Oldgren J, Yang S,
Alings M, Kaatz S, Hohnloser SH, Diener HC, Franzosi MG, Huber K, Reilly P, Varrone J,
Yusuf S. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and
younger patients with atrial fibrillation: an analysis of the Randomized Evaluation of Long-term
anticoagulant therapY (RE-LY) trial. Circulation. 2011;123:2363-2372.
24. Schulman S, Beyth RJ, Kearon C, Levine MN. Hemorrhagic complications of anticoagulant

18
Downloaded from by guest on April 27, 2014


DOI: 10.1161/CIRCULATIONAHA.113.002332

and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines (8th Edition). Chest. 2008;133:257S-298S.

25. Lim W, Dentali F, Eikelboom JW, Crowther MA. Meta-analysis: low-molecular-weight
heparin and bleeding in patients with severe renal insufficiency. Ann Intern Med. 2006;144:673684.
26. Hansen ML, Sorensen R, Clausen MT, Fog-Petersen ML, Raunso J, Gadsboll N, Gislason
GH, Folke F, Andersen SS, Schramm TK, Abildstrom SZ, Poulsen HE, Kober L, Torp-Pedersen
C. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in
patients with atrial fibrillation. Arch Intern Med. 2010;170:1433-1441.
27. Dans AL, Connolly SJ, Wallentin L, Yang S, Nakamya J, Brueckmann M, Ezekowitz M,
Oldgren J, Eikelboom JW, Reilly PA, Yusuf S. Concomitant Use of Antiplatelet Therapy with
Dabigatran or Warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy
(RE-LY) Trial. Circulation. 2013;127:634-640.
ffec
ff
ectt of
28. Holland LL, Brooks JP. Toward rational fresh frozen plasma transfusion: The eeffect
2006;126:133-1
-1
139
9.
plasma transfusion on coagulation test results. Am J Clin Pathol. 2006;126:133-139.
29. Hart RG, Diener HC, Yang S, Connolly SJ, Wallentin L, Reilly PA, Ezekowitz MD, Yusuf
patients during anticoagulation
anticoagu
gulation with warfarin or
S. Intracranial hemorrhage in atrial fibrillation patients
daabi
biga
gatr
ga
tran
tr

an
n: th
the RE
RE-L
-LY trial. Stroke. 2012;43:1511-1517.
2012;43:1551111-1517.
dabigatran:
RE-LY
30. F
libotte JJ,
J H
agan N
O
'Do
Donn
nnel
e l J, G
el
reen
nberg S
M, R
osan
os
andd J. Warfarin,
an
War
arfa
f rin, hematoma
fa
hemat

emattom
omaa ex
xpan
pansiion
30.
Flibotte
Hagan
N,, O'Do
O'Donnell
Greenberg
SM,
Rosand
expansion,
an
nd ou
ooutcome
tcomee of
o iintracerebral
nttraccerebrral
al hhemorrhage.
em
morrrh
r ag
age. Neurology.
Neuurolloggy. 2004;63:1059-1064.
2004
20
04;6
04
63:1105

1059-106
0664.
and
Ya ka M,, Minematsu
M ne
Mi
nem
matsuu K,
K Naritomi
Nar
arittomi H, Sakata
Sak
akaata T, Yamaguchi
Yama
Ya
magu
guch
c i T. Predisposing
Pre
redisp
spos
osin
ingg fact
ctor
o s fo
forr
31. Yasaka
factors
inttra
race

ceereebrral
a hemorrhage
hem
mor
o rh
rhag
ag
ge in patients
pat
atie
ient
ie
ntss treated
nt
trea
tr
eaate
tedd wi
with
th w
a fa
ar
fari
rin.
ri
n Thromb
n.
T ro
Th
romb

mb Haemost.
Hae
a most.
enlargementt of intracerebral
warfarin.
2003
20
03;8
;89:
9:27
2788-28
2833
2003;89:278-283.
32. Huttner HB, Schellinger PD, Hartmann M, Kohrmann M, Juettler E, Wikner J, Mueller S,
Meyding-Lamade U, Strobl R, Mansmann U, Schwab S, Steiner T. Hematoma growth and
outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral
anticoagulant therapy: comparison of acute treatment strategies using vitamin K, fresh frozen
plasma, and prothrombin complex concentrates. Stroke. 2006;37:1465-1470.
33. Davis SM, Broderick J, Hennerici M, Brun NC, Diringer MN, Mayer SA, Begtrup K, Steiner
T. Hematoma growth is a determinant of mortality and poor outcome after intracerebral
hemorrhage. Neurology. 2006;66:1175-1181.

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Table 1. Overview of patients and major bleeding events in the phase III long-term treatment trials.
Study

Randomized, N
Duration of treatment, months, median
Patients with major bleeds, N
Major bleeding events, N
Narratives available, N
Majorr bleeds, %/year*
Dabigatran
bigatran 150 mg BID
Warfarin,
rfarin, INR 2.0-3.0

RE-LY
18113
24
1162
1378
1006
3.32

2.71†
3.57

RE-COVER
2539
6
44
47
46

RE-COVER II

2568
6
37
40
28

RE-MEDY
2856
18
38
40
39

RE-SONATE
1343
6
2
2
2

3.2
3.8

2.4
3.4

0.77
1.44

0.6

0.6
NA‡

BID – twice daily; INR – international normalized ratio; NA – not applicable. *The differences between dabigatran 150 mg bid and warfarin were not
cally different in any of the studies. †For dabigatran 110 mg BID, which only was used in the RE-LY trial, % major bleeds/year was significantly low
statistically
lower
ith warfarin (relative risk, 0.80; 95% CI 0.69–0.93). ‡The comparator in this study was placebo and there were no major bleedings in that group.
than with

Tablee 2.. Th
Thee characteristics
ch
har
arac
racteri
e sttic
ics
cs of
o the 1,034 patients with 1,121 majorr bleeding
b ee
bl
eeding events and reviewed
rev
e iewe
wed
ed narratives.
n rratives.
na

Patients
nts
t rrandomized
a domizedd an
an
and tr
ttreated,
reate
a d,, N
Patients
nts w
with
ith
it
th ma
majo
major
jorr bl
jo
bbleed,
eed,
ee
d, N
Age, years,
yeaars
rs,, mean
mean ((SD)
S )
SD
Male ssex,

ex, N (%
ex
(%))
Body weight, kg (SD)
D
D)
Creatinine,
inine
i ȝmol/
ȝmol/L,
l/L
L m
median
edi
dian ((range)
range))
Creatinine clearance, median (range)
Aspirin, N (%)
Clopidogrel, N (%)
Triple therapy, N (%)
NSAID

D 110
110 mg
m

D 1150
50 m
mg
g

W
Wa
Warfarin
rffar
arin
rin

66,015
,0
015
5
2622
26
75
75.9
.99 ((6.6)
6 6)
6.
170
170 (64.9)
(644.9)
(6
9)
81.4
8 .44 (18.8)
81
(18.8
188.88)
1066 (4

10
(44
(44-968)
4 96
968)
8)
52 (5-155)
93 (35.5)
3 (1.1)
10 (3.8)
39 (15.9)

110,740
0,740
4
3365
36
5
775.1
5.11 (7
5.
((7.8)
7.8)
8)
234
234 (64.1)
(64.1)
1)
82.1
82.1 ((20.2)

2 .22)
20
105
105 ((43-800)
43 800
00))
55 (5-199)
101 (27.7)
9 (2.5)
13 (3.6)
42 (11.5)

110,002
0,002
4077
40
71.8
71
1.8
8 ((10.3)
10.3
.3)
3)
268(65.9)
268(
26
8(65
8(
65.9)
9)

81.2
81.2
2 ((20.5)
20.5))
20
96 ((17-577)
17 577
77))
62 (7-239)
100 (24.6)
7 (1.7)
14 (3.4)
34 (8.4)

P
P-value
-val
alue
lue
D 110
1 0 vs D 150
11
150
50

P-va
P-value
P
v lue*
D vs

v W

00.22
.22
0.83
0.83
83
0.62
0.
62

<0
<0.0001
0.0
.000
000
0
0.67
0.67
67
0.63

0.05
0.040
0.38
0.92
0.21

<0.0001
0.026

1.0
0.93
0.023

D110 – dabigatran 110 mg twice daily; D150 – dabigatran 150 mg twice daily; D – dabigatran; W - warfarin; SD – standard deviation; NSAID – non-steroid
anti-inflammatory agent. *The tests used were t-test for age and body weight, Pearson’s chi-square for sex, aspirin, clopidogrel and triple therapy or Fisher’s
exact test when a numerator was less than 10.

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Table 3. Hemostatic products used for major bleeding, as derived from the RE-LY database.
P-value
D 110 vs
D 150

P-value
D vs
warfarin

P-value
D 110 vs
warfarin

P-value
D 150 vs
warfarin

0.20

0.002

0.06

<0.001

D 110 mg
342 (100)
194 (56.7)

D 150 mg
399 (100)
245 (61.4)

Dabigatran
741 (100)
439 (59.2)

Warfarin
421 (100)
210 (49.9)

Blood transfused, units, median (IQR)
Patients
nts treated with FFP, n (%)
FFP transfused,
ransfused, units (median, IQR)

Patients
nts treated with cryoprecipitate, n (%)
Cryoprecipitate
precipitate transfused, units (median,
IQR)

2.0 (2.0)
61 (17.8)
2.0 (2.0)
3 (0.9)
1.0 (0.0)

3.0 (2.0)
86 (21.6)
4.0 (2.5)
5 (1.3)
2.0 (3.0)

3.0 (2.0)
147 (19.8)
4.0 (2.0)
8 (1.1)
2.0 (3.0)

3.0 (2.0)
127 (30.2)
4.0 (2.0)
7 (1.7)
2.5 (3.0)

0.11
0.21
.
0.62
.

0.35
<0.001
<0.0
.001
01
.
0.40
40
.

0.11
<0.001
<0.0
<0
.001
.0
01
.
0.34
0
.34
34
.

0.88
0.005
.
0.63
.

Patients
nts ttreated
reat
re
atted w
with
ith
it
h pl
plat
platelets,
a elet
at
etts,
s n ((%)
%)
Platelets
etss tr
et
ttransfused,
ansf
an
sfused
d, un

uunits
i s (med
it
(median,
mediaan, IQR)
Patients
nts
ts ttreated
reat
re
ea ed with vi
vita
vitamin
t mi
min
n K,
K n ((%)
%)
Patients
nts
t tre
treated
r ated with PCC,
re
C, n (%)
%
Patients
nts
t ttreated
reat

re
ea ed with reco
recombinant
c mbin
bi an
a t factor
a o
VIIa, n (%
(%))

13 (3.8)
2.5 (1.5)
29 ((8.5)
8.5)
8.5)
3 (0.9)
(0.9
(0
. )
.9
1 (0.3)
(0
0.3))

15 (3.8)
2.0 (3.0)
4 (10.3)
41
(10
10.3

.3)
3)
2 (0.5)
(0.5)
5
7 (1.8)
(1.8)
8

2 (3.8)
28
2.0
.0 (2.0)
700 (9.4)
7
4))
5 (0.7)
(0.7)
7)
8 (1.1)
(1.11)

20 (4.8)
3.0 (4.0
(4.0)
0)
1155 (27.3)
1
11
(27.

(2
7 3)
5 (1.2)
(1.2)
3 (0.7)
(0.7)

0.98
0
.98
9
.
0.40
0.
4
40
0.53
0
0.
53
53
0.05
0
0.
05
05

0.42
.
<0.001

<0
.001
001
0
0.36
0.
36
6
0.53
0
0.
53

0.52
.
<0.001
<
<0
.0001
0.68
0.68
0.42
0
0.
42

0.48
.
<0.001
<

0.29
0.17

0 (0.0)
(0.0
(0
.00)

3 (0.8)
(0.8
(0
.8))
.8

3 (0.4)
(0.4)
4)

4 (1.0)
(1.0)
0)

0.11
0.11

0.25
0.25

0.07
0

0.
07

0.76

Patients with major bleeds, n (%)
Patients treated with blood transfusion, n
(%)

Patients
nts ttreated
reat
re
eat
ated
ed w
with
ith
it
h co
coag
coagulation
agul
ulat
ul
atio
at
ion
io
n fa

fact
factor
ctor
ct
or
replacement,
emen
e t, n (%)
(%)

D110 – dabigatran 110 mgg twice
twi
w cee daily;
dail
da
i y; D150
il
D15
1 0 – dabigatran
dabi
da
b gaatr
tran
an 150
150 mg
mg twice
tw
wic
icee daily;
dail

da
ily;
il
y; FFP
FFP – fresh
f es
fr
e h frozen
froz
fr
ozzen
e plasma;
plaasm
sma;
a IQR
a;
QR – interquartile
int
nter
erqu
er
quar
qu
a ti
ar
tilee range;
ran
angge;
e PCC
PCC

C – prothrombin
complex
ex concentrate

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DOI: 10.1161/CIRCULATIONAHA.113.002332

Table 4. Short-term consequences of major bleeding, as derived from the RE-LY database.

Patients with major bleeds, n (%)
Major bleeding events, n
Hospitalization, event (%)*
Length of stay, days, mean (SD)
Nightss in ICU/CCU, mean (SD)
Nightss in step-down unit, mean (SD)
Patients
nts with major bleed requiring surgery,
n (%)
Patients
nts with major bleed requiring surgery
or resulting
ulting in death, n (%)
Decrease
ase in Hgb, g/L,, mean (SD) – from
baseline
ne tto
o ti

time
m ooff bl
me
blee
bleeding
e di
ee
d ngg
Decrease
asee in
in Hgb
Hg g/L,
g//L, median
mediaan (IQR)
(IQR
(I
QR) – from
time off blee
bleeding
e ding to lowe
ee
lowest
westt H
we
Hgb
gb
Discontinuation
ntinu
nuation
u

of study
ym
medication,
e iccati
ed
tion,
ion n (%)
(%)
Discontinuation
ntinu
nuation
u
of ASA, n (%)
(%)
(%
Discharge
arg
r e de
ddestination,
stination,
n, n (% of
hospitalizations)
aliz
al
izat
iz
a io
ions
n )†
ns

Home
me
Long-term
g te
gterm
rm ffacility
acil
ac
ilit
il
ity
it
y
Another
ther hospital
mRS at ppresentation,
rese
re
sent
ntat
atio
ion,
n, m
median
edia
ed
ian
n (I
(IQR
(IQR)

QR))‡
mRS at follow up, median (IQR) ‡
Difference initial-final mRS, median (IQR) ‡

P-value
D 110 vs
D 150

P-value
D vs
warfarin

P-value
D 110 vs
warfarin

P-value
D 150 vs
warfarin

0.002
0.61
0.02
0.39
0.09

0.89
0.48
0.01
0.84

0.
844
0.17
0.
17
17

0.11
0.36
0.001
0.
.00
001
1
0.75
0
0.
75
0.05
0
0.
05

0.10
0.68
0.10
0.59
0.76

D 110 mg

342 (100)
406
208 (51.2)
8.1 (8.0)
1.1 (3.2)
1.1 (2.5)
34 (9.9)

D 150 mg Dabigatran
399 (100)
741 (100)
489
895
302 (61.8) 510 (57.0)
8.5 (9.8)
8.4 (9.1)
1.9 (4.9)
1.6 (4.3)
0.9 (2.5)
1.0 (2.5)
56 (14.0)
90 (12.1)

Warfarin
421 (100)
483
273 (56.5)
8.9 (9.8)
2.7 (6.6)
1.0 (2.7)

63 (15.0)

56 (16.4)

76 (19.0)

132 (17.8)

94 (22.3)

0.38

0.06

0.04

0.26

39.7 (29.2) 36.5 (25.4)

38.0 (27.2)

30.7 (24.7)

0.43

0.02

0.02

0.10

0.0 (16.0)

0.0 (14.0))

0.00 (14.0))
0
0.

1.0 (18.0)
0)

0.84
0
.84
84

0.07

0.15

0.09

42 (12.3)
(12
1 .3
.3 )
16 (4
(4.7)

4.7)
7)

53 (13.3)
5
(13
3.3)
3)
20 ((5.0)
5.0))

955 (12.8)
(122.8
. )
36
3
6 (4.9)
9))

622 (14.7)
(14
14.7))
15
1
5 ((3.6)
3.6)
.

0.68
0.68

0
68
0.83
0
0.
83
83

0.36
0.
366
0.30
0.
300

0.33
0.
3
33
0.44
0
0.
44

0.55
0.30

152
15
2 (73.1)

(73.
(7
3 1))
28 (13.5)
(13.5
.5)
5)
10 ((4.8)
4.8)
4.
8)
5 (2)
(2)
6 (3)
0 (1)

234
23
4 (77.5)
(77
(7
7.5)
7.5)
32 (10.6)
(10.6
.6)
6)
13
3 ((4.3)
4 3)

4.
6 (1)
(1)
6 (2)
0 (2)

386
38
6 (75.7)
( 5.
(7
5.7)
7)
60 (11.8)
(11.8
.8)
8)
1 ((2.5)
13
2 5))
2.
6 (1)
(1)
6 (0)
0 (0)

199
19
9 (72.9)
(72

2.9)
9)
35 (12.8)
(12.8
.8)
8)
1 ((6.2)
17
6.2)
6.
2
5 (3)
(3)
6 (4)
0 (1)

0.29
0
.29
0.33
0.33
0.83
0.
83
0.13
0.
13
0.45
0.78

0.39
0
.39
39
0.73
0.73
0.31
0
0.
31
0.10
0.
10
0.10
0.97

1..00
1.00
1
00
0.89
0.89
0.55
0.70
0.
70
0.52
0.80

0.21

0.44
0.35
0.03
0.11
0.81

D110 – dabigatran 110 mg twice daily; D150 – dabigatran 150 mg twice daily; IQR – interquartile range; ICU – intensive care unit; CCU – coronary care unit;
Hgb – hemoglobin; ASA – acetylsalicylic acid, mRS – modified Rankin Scale. *Pertaining to the patients that were hospitalized for the major bleed.
Hospitalization is reported for a major bleeding event, if admission to hospital was between 1 day before event and 7 days after the event. †In about 10% of cases
the discharge destination was not recorded. ‡The mRS evaluations were only for patients with intracranial hemorrhage.

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DOI: 10.1161/CIRCULATIONAHA.113.002332

Figure Legend:

Figure 1. 30-day mortality rate after a major bleeding event.

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