1. No category

Intracranial Hemorrhage in Atrial Fibrillation Patients During Anticoagulation With
Warfarin or Dabigatran: The RE-LY Trial
Robert G. Hart, Hans-Christoph Diener, Sean Yang, Stuart J. Connolly, Lars Wallentin, Paul A.
Reilly, Michael D. Ezekowitz and Salim Yusuf
Stroke. 2012;43:1511-1517; originally published online April 5, 2012;
doi: 10.1161/STROKEAHA.112.650614
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Copyright © 2012 American Heart Association, Inc. All rights reserved.
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Intracranial Hemorrhage in Atrial Fibrillation Patients
During Anticoagulation With Warfarin or Dabigatran
The RE-LY Trial
Robert G. Hart, MD; Hans-Christoph Diener, MD; Sean Yang, MSc; Stuart J. Connolly, MD;
Lars Wallentin, MD; Paul A. Reilly, PhD; Michael D. Ezekowitz, DPhil; Salim Yusuf, DPhil
Background and Purpose—Intracranial hemorrhage is the most devastating complication of anticoagulation. Outcomes
associated with different sites of intracranial bleeding occurring with warfarin versus dabigatran have not been defined.
Methods—Analysis of 18 113 participants with atrial fibrillation in the Randomized Evaluation of Long-term anticoagulant
therapY (RE-LY) trial assigned to adjusted-dose warfarin (target international normalized ratio, 2–3) or dabigatran (150
mg or 110 mg, both twice daily).
Results—During a mean of 2.0 years of follow-up, 154 intracranial hemorrhages occurred in 153 participants: 46%
intracerebral (49% mortality), 45% subdural (24% mortality), and 8% subarachnoid (31% mortality). The rates of
intracranial hemorrhage were 0.76%, 0.31%, and 0.23% per year among those assigned to warfarin, dabigatran 150 mg,
and dabigatran 110 mg, respectively (P⬍0.001 for either dabigatran dose versus warfarin). Fewer fatal intracranial
hemorrhages occurred among those assigned dabigatran 150 mg and 110 mg (n⫽13 and n⫽11, respectively) versus
warfarin (n⫽32; P⬍0.01 for both). Fewer traumatic intracranial hemorrhages occurred among those assigned to
dabigatran (11 patients with each dose) compared with warfarin (24 patients; P⬍0.05 for both dabigatran doses versus
warfarin). Independent predictors of intracranial hemorrhage were assignment to warfarin (relative risk, 2.9; P⬍0.001),
aspirin use (relative risk, 1.6; P⫽0.01), age (relative risk, 1.1 per year; P⬍0.001), and previous stroke/transient ischemic
attack (relative risk, 1.8; P⫽0.001).
Conclusions—The clinical spectrum of intracranial hemorrhage was similar for patients given warfarin and dabigatran.
Absolute rates at all sites and both fatal and traumatic intracranial hemorrhages were lower with dabigatran than with warfarin.
Concomitant aspirin use was the most important modifiable independent risk factor for intracranial hemorrhage. (Stroke.
2012;43:1511-1517.)
Key Words: atrial fibrillation 䡲 intracranial hemorrhage 䡲 intracerebral hemorrhage 䡲 warfarin 䡲 anticoagulation
䡲 subdural hematoma 䡲 dabigatran
I
ntracranial hemorrhage is the most feared complication of
warfarin anticoagulation in older patients with atrial fibrillation and is responsible for the bulk of disability and death
from anticoagulation-associated bleeding.1 About two thirds
of intracranial hemorrhages during warfarin anticoagulation
are intracerebral hemorrhages, and most of the remainder are
subdural hematomas. In recent randomized trials testing
antithrombotic therapies in atrial fibrillation patients, the
primary efficacy outcome included intracerebral hemorrhages
combined with ischemic strokes, whereas subdural hematomas were separately categorized with major hemorrhage.2– 6
The morbidity and mortality of different sites and precipitants
of intracranial hemorrhage have been incompletely characterized in these studies.
In the Randomized Evaluation of Long-term anticoagulant
therapY (RE-LY) randomized trial, the incidence of intracerebral hemorrhage in atrial fibrillation patients was significantly lower with dabigatran, a novel oral direct thrombin
inhibitor, compared with warfarin.4 Little is known about the
full clinical spectrum of intracranial bleeding in atrial fibrillation patients given dabigatran. The absence of an antidote to
reverse emergently its antihemostatic effect has prompted
concern that intracranial hemorrhages with dabigatran could
carry a worse prognosis than could those associated with
Received January 11, 2012; accepted February 22, 2012.
Louis Caplan, MD, was the Guest Editor for this paper.
From the Population Health Research Institute (R.G.H., S.Ya., S.J.C., S.Yu.), McMaster University and Hamilton Health Sciences, Hamilton, Ontario,
Canada; Department of Neurology (H.-C.D.), University Duisburg-Essen, Essen, Germany; Uppsala Clinical Research Centre (L.W.), Uppsala University,
Uppsala, Sweden; Boehringer Ingelheim (P.A.R.), Ridgefield, CT; Lankenau Institute for Medical Research (M.D.E.), Wynnewood, PA.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.111.
650614/-/DC1.
Correspondence to Robert G. Hart, MD, McMaster University, 237 Barton Street East, HGH – DBCVSRI C3-110, Hamilton, Ontario, Canada L8L
2X2. E-mail [email protected]
© 2012 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.112.650614
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by guest on September 9, 2014
1511
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Stroke
June 2012
hemorrhage within a larger area of apparent infarction and/or
appearance of hemorrhage on follow-up imaging. These policies
resulted in 1 intracranial hemorrhage per patient categorized at
a single site of bleeding; the single exception was a patient with a
traumatic intracerebral hemorrhage who several months later had a
spontaneous subdural hematoma.
For reproducibility of classification as traumatic with differing
amounts of clinical information, we applied specific criteria: the
level of trauma must have been that which would have warranted
immediate medical attention. Examples:
Figure. Sites of intracranial bleeding.
warfarin. We analyze intracranial hemorrhages occurring
during anticoagulation, including sites, rates, risk factors,
associated trauma, and outcomes among participants in the
RE-LY trial.
Methods
The design and main results of the RE-LY trial have been published.4,7,8 The trial was funded by Boehringer Ingelheim and was
coordinated by the Population Health Research Institute (Hamilton,
Canada). Between 2005 and 2007, 18 113 patients from 951 sites in
44 countries who had documented atrial fibrillation and at least 1
additional stroke risk factor were randomized to receive, in a blinded
fashion, fixed doses of dabigatran—110 mg or 150 mg twice daily;
or, they were given open-label, adjusted-dose warfarin with a target
international normalized ratio of 2.0 to 3.0.4
Intracranial hemorrhages were identified by local investigators
and were submitted for central adjudication by neurologists.4
Source documents were translated into English, and information
about antithrombotic therapy was expunged. Neuroimaging confirmation was present in 97% of intracranial hemorrhages: computed tomography (CT; 87%), magnetic resonance imaging (MRI;
3%), or both (7%); the diagnosis was based on spinal fluid
examination in 1 patient. For this project, 2 stroke neurologists
(R.G.H., H-C.D.) independently re-evaluated each case to identify the primary site of intracranial bleeding by review of imaging
reports, presence of associated head trauma, and neurological
outcomes, with differences resolved by consensus. Details about
reversal of anticoagulation were inconsistently available in the
source documents.
Intracranial hemorrhage was classified by the site of bleeding
into intracerebral hemorrhages (classified as hemorrhagic
strokes in the RE-LY main results), subdural hematomas, and
subarachnoid hemorrhages based on imaging features from review of local interpretation of brain imaging (Figure). Patients
with traumatic intracranial hemorrhage frequently had multiple
sites of hemorrhage and were categorized according to the most
clinically important site. Traumatic hemorrhagic contusions were
classified as traumatic intracerebral bleeds. For patients with
massive head trauma and multiple sites of intracranial bleeding
for whom the most clinically relevant site could not be determined, the hemorrhages were analyzed as intracerebral hemorrhages if present (n⫽3) and otherwise as subdural hematomas
(n⫽2). Large intracerebral hemorrhages with secondary rupture
into the ventricular system were categorized as intracerebral, as
well as the single patient with a primary intraventricular hemorrhage. Patients with secondary hemorrhagic transformation of
ischemic strokes were excluded based on consideration of neuroimaging reports and clinical scenario— evidence of mottled
a. Spontaneous subdural hematoma: the patient slipped and fell at
home, but did not seek medical attention. One week later,
headache and mild hemiparesis led to CT and diagnosis of
chronic subdural hematoma.
b. Traumatic subdural hematoma: the patient fell at home and
was taken to a local emergency clinic where he was
evaluated, treated for contusions, and released. One week
later, headache led to CT and diagnosis of subacute subdural
hematoma.
c. If a subdural hematoma had CT features of chronicity (eg,
hypodense relative to brain) at the time of evaluation for acute
head trauma, it was assumed not to be the result of the acute
episode of head trauma and was classified as spontaneous.
Using these criteria, diagnosis was influenced by access to urgent
medical care and likely resulted in misclassification of some traumarelated subdural hematomas as spontaneous. There were 7 patients
with neuroimaging evidence of intracranial hemorrhage (3 intracerebral hemorrhage, 4 subdural), but too little clinical information to
ascertain the role of trauma, and these patients were arbitrarily
classified as spontaneous. Outcomes were categorized as full recovery, survival with neurological deficit, or fatal based on all available
follow-up information.
Statistical Methods
All analyses are based on the intention-to-treat paradigm unless
otherwise designated. The t test was used for the continuous
variables, and ␹2 test was used for categorical variables. The
analyses of independent predictors of intracranial hemorrhage were
based on Cox proportional hazards regression models, which considered variables that had probability values ⬍0.1 by univariate
analysis; only those that were significant are presented. Hazard
ratios, 95% confidence intervals, and nominal probability values
were calculated for outcome events comparing treatment arms.
Mortality from intracranial hemorrhage between treatments was
compared by ␹2 test. All analyses were performed with SAS version
9.1 (SAS Inc). Two-sided probability values ⬍0.05 were considered
statistically significant. No adjustments were made for multiple
comparisons.
Results
Among all participants, the mean age was 71 years, 20% had
previous stroke or transient ischemic attack (TIA), 50%
received warfarin before study entry, and blood pressure at
entry averaged 131/77 mm Hg. Concomitant aspirin was used
at the first study follow-up visit by 28% of patients, and the
time-in-therapeutic-range for those assigned to warfarin averaged 64%, with a mean achieved international normalized
ratio of 2.41.
Intracranial Hemorrhage
During follow-up, 154 intracranial hemorrhages occurred in
153 patients, with an overall 30-day mortality of 36% (Table
1). Intracranial hemorrhages included intracerebral hemorrhages (46%, with 49% mortality), subdural hematomas
(45%, with 24% mortality), and subarachnoid hemorrhages
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Hart et al
Brain Hemorrhage With Warfarin or Dabigatran
Table 1. Intracranial Hemorrhages in the RE-LY Trial: Sites of
Bleeding and Associated Mortality*
All sites
All
(Mortality)
Spontaneous
(Mortality)
Traumatic
(Mortality)
46 (24%)
154 (36%)
108 (42%)
Intracerebral
71 (49%)
63 (52%)
8 (25%)
Subdural
70 (24%)
39 (21%)
31 (29%)
Subarachnoid
13 (31%)
6 (67%)
7 (0%)
*See Methods for definition of spontaneous vs traumatic. One intracranial
hemorrhage per patient except 1 patient who was assigned to dabigatran 110
mg twice daily and experienced syncope with head trauma; CT showed an area
of parietal contusion with a small area of hemorrhage within it. Dabigatran was
discontinued for 1 month and then restarted. Three months later, he presented
with confusion and was found to have large bilateral subdural hematomas, with
no recorded history of head trauma. He was transfused with multiple units of
fresh-frozen plasma, and bilateral craniotomy was undertaken for drainage.
Postoperative course was complicated by seizures and pneumonia, and he
died.
(8%, with 31% mortality; Figure 1). Associated trauma was
present in 30% of intracranial hemorrhages, but differed by
site: 11% of intracerebral hemorrhages were classified as
traumatic versus 44% of subdural hematomas (Table 1). Of
Table 2.
1513
108 spontaneous intracranial hemorrhages, 58% were intracerebral hemorrhages (52% mortality), 36% were subdural
hematomas (21% mortality), and 6% subarachnoid hemorrhages (67% mortality).
Compared with those without intracranial hemorrhage,
patients with intracranial hemorrhage were, on average, older
(P⬍0.001) with a history of stroke or TIA (P⫽0.001), more
often took aspirin during follow-up (P⫽0.001), less often
had heart failure (P⫽0.02), and had, on average, lower
estimated creatinine clearances (P⬍0.001; Table 2); these
differences were consistent between treatment arms
(online-only, Supplemental Data, Appendix I). By multivariate analysis, assignment to warfarin (relative risk [RR],
2.9; Pⱕ0.001), aspirin use during follow-up (RR, 1.6;
P⫽0.01), age (RR, 1.1 per year; P⬍0.001), previous
stroke/TIA (RR, 1.8; P⫽0.001) and white race (RR, 0.68;
P⫽0.02) were independent predictors of intracranial
bleeding (Table 3). By on-treatment analysis, the independent predictors were similar, except the relative risk
associated with assignment to warfarin was larger (RR,
3.8; P⫽0.001) and white race was no longer significant
(online-only, Supplemental Data, Appendix III).
Features of Participants With Intracranial Hemorrhage*
P Value†
Spontaneous
Intracerebral
Hemorrhage‡
(n⫽63)
⬍0.001
No Intracranial
Hemorrhage
(n⫽17 960)
Any Intracranial
Hemorrhage
(n⫽153)
Mean age (y)
71.5
75
Men (%)
64%
65%
NS
White (%)
70%
63%
Features
P Value§
Subdural
Hematomas㛳
(n⫽70)
P Value¶
74
0.01
75
⬍0.001
54%
NS
71%
NS
NS
62%
NS
64%
NS
Hypertension (%)
79%
84%
NS
86%
NS
81%
NS
Diabetes (%)
23%
26%
NS
27%
NS
24%
NS
Heart failure (%)
32%
24%
0.02
19%
0.02
24%
NS
Coronary artery disease (%)
29%
28%
NS
19%
NS
34%
NS
Previous stroke/TIA (%)
20%
31%
0.001
40%
⬍0.001
27%
NS
Paroxysmal AF (%)
33%
36%
NS
29%
NS
43%
NS
Previous VKA use (%)**
50%
53%
NS
51%
NS
53%
NS
Systolic BP at entry (mean; mm Hg)
131
131
NS
133
NS
130
NS
Tobacco smoking (%)
51%
54%
NS
48%
NS
59%
NS
Alcohol use (%)
33%
28%
NS
30%
NS
26%
NS
History of falls (%)
11%
16%
NS
10%
NS
17%
NS
Assigned warfarin (%)
33%
59%
⬍0.001
67%
⬍0.001
51%
0.001
Aspirin use before hemorrhage (%)
32%††
42%
0.006
44%
0.03
39%
NS
Mean creatinine clearance (ml/min;
Cockcroft-Gault)
73
62
⬍0.001
62
⬍0.001
63
⬍0.001
NS indicates not statistically significant (Pⱖ0.05); TIA, transient ischemic attack; AF, atrial fibrillation; VKA, vitamin K antagonist; BP, blood pressure.
*All treatment arms; see online-only Supplemental Data Appendix I for patients assigned to warfarin and dabigatran separately.
†Comparing no intracranial hemorrhage with any intracranial hemorrhage.
‡Eight traumatic intracerebral hemorrhages are not included.
§Comparing spontaneous intracerebral hemorrhage with no intracranial hemorrhage.
㛳There were no significant differences in features between patients with spontaneous subdural hematomas (n⫽39) and traumatic subdural hematomas (n⫽31;
online-only Supplemental Data Appendix II), and all subdural hematomas are considered together.
¶Comparing subdural hematomas with no intracranial hemorrhage.
**Total lifetime use ⬎62 d.
††For participants without intracranial hemorrhages, the fraction using aspirin at any follow-up visit before the mean time-to-intracranial-hemorrhage is used.
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1514
Stroke
June 2012
Table 3. Features Independently Predictive of
Intracranial Hemorrhage*
Feature
Relative
Risk
P
Value
Age (per y)
1.1
⬍0.001
White
0.68
0.02
Previous stroke/TIA
1.8
0.001
Assigned warfarin
2.9
⬍0.001
Aspirin use
1.6
0.01
All participants
All intracranial hemorrhages
(n⫽153)
Spontaneous intracerebral
bleeds (n⫽63)
Subdural hematomas
(n⫽70)
Age (per y)
1.04
0.02
Previous stroke/TIA
2.7
⬍0.001
Assigned warfarin
4.1
⬍0.001
Aspirin use
1.8
0.02
Age (per y)
1.1
0.001
Intracerebral Hemorrhage
Assigned warfarin
2.1
0.002
Age (per y)
1.1
0.001
White
0.6
0.04
Previous stroke/TIA
2.0
0.003
Aspirin use
1.6
0.04
TTR
0.99
0.05
Previous stroke/TIA
2.9
0.001
Aspirin use
2.0
0.03
Age (per y)
1.1
0.04
Age (per y)
1.1
0.002
Age (per y)
1.1
0.003
Male
2.5
0.03
Dabigatran dose
150 mg vs 110 mg
2.4
0.02
Most intracerebral hemorrhages (89%) were spontaneous. Of
traumatic intracerebral hemorrhages (n⫽8), almost all were
associated with major head trauma. Traumatic intracerebral
hemorrhages usually consisted of dense hematoma within
more widespread areas of cerebral contusion, and the contribution of the hematoma to neurological status and outcome
was difficult to define.
Independent predictors of developing spontaneous intracerebral bleeding were: assignment to warfarin (RR, 4.1;
P⬍0.001), previous stroke/TIA (RR, 2.7; P⬍0.001), aspirin
use (RR, 1.8; P⫽0.02), and age (1.04 per year; P⫽0.02;
Table 3), with similar independent predictors from ontreatment analysis (online-only, Supplemental Data, Appendix III). Aspirin use and previous stroke/TIA predicted
intracerebral hemorrhage in 42 warfarin-assigned patients,
but there were no significant predictors for the 21 events in
those assigned dabigatran (Table 3).
The rate of spontaneous intracerebral hemorrhage was
0.36% per year (n⫽42) among those assigned to warfarin and
was substantially lower for those assigned to dabigatran 150
mg (0.09% per year, n⫽11; RR, 0.26; 95% CI, 0.13– 0.50)
and dabigatran 110 mg (0.08% per year, n⫽10; RR, 0.23;
95% CI, 0.12– 0.47; Table 4). The mortality associated with
spontaneous intracerebral hemorrhage averaged 52%, with no
significant differences between treatment arms (Table 5).
Fatal spontaneous intracerebral bleeding occurred in 19
patients assigned to warfarin versus 7 patients each with
dabigatran 150 mg and 110 mg (P⬍0.01 for both comparisons with warfarin).
Considering locations of spontaneous intracerebral bleeding, patients with hemorrhage in the basal ganglia/thalamus
were, on average, younger (P⫽0.04) and more often had
diabetes (P⫽0.02) compared with those with lobar bleeding
(online-only, Supplemental Data, Appendix VI).
Warfarin-assigned
All intracranial hemorrhages
(n⫽90)
Spontaneous intracerebral
bleeds (n⫽42)
Subdural hematomas
(n⫽36)
Dabigatran-assigned
(both dosages)
All intracranial hemorrhages
(n⫽64)†
Spontaneous intracerebral
bleeds (n⫽21)
Subdural hematomas
(n⫽34)
treatment arms (36% warfarin, 35% dabigatran 150 mg, 41%
dabigatran 110 mg; Table 5). Fatal intracranial bleeding
occurred in 32 patients assigned to warfarin versus 13
patients and 11 patients with dabigatran 150 mg and 110
mg, respectively (P⬍0.01 for both comparisons with
warfarin). Independent predictors of intracranial hemorrhage with warfarin were the same as those listed above with
the addition of time-in-therapeutic-range (P⫽0.05; Table 3).
Only age (RR, 1.06 per year; P⫽0.002) was independently
predictive of intracranial hemorrhage among dabigatranassigned patients (Table 3). The relative risk of intracranial
hemorrhage was lower with dabigatran (either dose) compared with warfarin among subgroups defined by independent predictors of intracranial hemorrhage (online-only, Supplemental Data, Appendix V).
None
TIA indicates transient ischemic attack; TTR, time-in-therapeutic-range (INR,
2–3).
*The models included variables that had P values of ⬍0.1 by univariate
analysis (Table 2, online-only Supplemental Data Appendix I) except for
creatinine clearance. When creatinine clearance was included, age, previous
stroke/TIA, and white race were no longer significant, and creatinine clearance
(per increment by 10 mL/min) was significantly predictive of all intracranial
hemorrhage (RR, 0.88; P⫽0.01) and spontaneous intracerebral hemorrhage
(RR, 0.86; P⫽0.04) in all participants, of all intracranial hemorrhage (RR, 0.89;
P⫽0.05) in warfarin-assigned patients, and of spontaneous intracerebral
hemorrhage (RR, 0.81; P⫽0.05) in dabigatran-assigned patients. Intention to
treat analysis; for on-treatment analysis of independent predictors, see
online-only Supplemental Data Appendix III.
†Aspirin use was associated with a relative risk of 1.5 (95% CI, 0.89 –2.5).
The rate of intracranial hemorrhage was 0.76% per year
among those assigned to warfarin and was significantly lower
for those assigned to dabigatran 150 mg (0.31% per year; RR,
0.40; 95% CI, 0.27– 0.59) and dabigatran 110 mg (0.23% per
year; RR, 0.30; 95% CI, 0.19 – 0.45; Table 4). Mortality
associated with intracranial hemorrhage was similar between
Subdural Hematomas
Subdural hematomas accounted for 45% of intracranial
hemorrhages and were associated with trauma in 44%—an
identical percentage for warfarin-assigned (44%, 16/36)
and dabigatran-assigned (44%, 15/34) participants (Table
4). Risk factors for subdural hematomas categorized as
spontaneous (n⫽39) and traumatic (n⫽31) were not dif-
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Hart et al
Table 4.
Brain Hemorrhage With Warfarin or Dabigatran
1515
Sites and Rates of Intracranial Hemorrhage by Treatment Assignment*
Dabigatran 150 mg
vs Warfarin
Dabigatran 110 mg
vs Warfarin
Dabigatran 150 mg
vs 110 mg
Warfarin
N/Rate (%/y)
Dabigatran
150 mg
N/Rate (%/y)
Dabigatran
110 mg
N/Rate (%/y)
RR (95% CI)
P Value
RR (95% CI)
P Value
RR (95% CI)
P Value
All intracranial
(n⫽154)
90/0.76
37/0.31
27/0.23
0.40 (0.27– 0.59)
⬍0.001
0.30 (0.19 – 0.45)
⬍0.001
1.4 (0.83–2.2)
NS
Intracerebral (n⫽71)
46/0.39
11/0.09
14/0.12
0.23 (0.12–0.45)
⬍0.001
0.30 (0.16–0.54)
⬍0.001
0.78 (0.35–1.7)
NS
42/0.36
11/0.09
10/0.08
0.26 (0.13–0.50)
⬍0.001
0.23 (0.12–0.47)
⬍0.001
1.1 (0.46–2.6)
NS
4/0.03
0/0.0
4/0.03
0.0
NS
0.99
NS
0.0
NS
Subdural (n⫽70)
36/0.31
24/0.20
10/0.08
0.65 (0.39–1.1)
0.10
0.27 (0.12–0.55)
⬍0.001
2.4 (1.1–5.0)
0.02
Spontaneous
20/0.17
14/0.12
5/0.04
0.68
NS
0.25 (0.09–0.66)
0.005
2.8 (1.0–7.7)
NS
Traumatic
16/0.14
10/0.08
5/0.04
0.61
NS
0.31 (0.11–0.84)
0.02
2.0 (0.68–5.8)
NS
8/0.06
2/0.02
3/0.03
0.24 (0.05–1.2)
0.07
0.37
NS
0.66 (0.11–4.0)
NS
Spontaneous
4/0.03
1/0.01
1/0.01
0.24
NS
0.24
NS
0.99 (0.06–16)
NS
Traumatic
4/0.03
1/0.01
2/0.02
0.25
NS
0.50
NS
0.50 (0.04–5.5)
NS
Spontaneous
Traumatic
Subarachnoid
(n⫽13)
RR indicates relative risk; NS, not statistically significant (P⬎0.05).
*See Methods for criteria for spontaneous vs traumatic. Rates calculated using the denominator of exposure for the specific type of intracranial hemorrhage by
the intention-to-treat paradigm. On-treatment results were similar and are found in the online-only Supplemental Data Appendix IV.
ferent (online-only, Supplemental Data, Appendix II),
and all subdural hematomas were considered together in
subsequent analyses. The identification of subdural hematomas was distributed relatively evenly throughout
follow-up in all treatment arms, and paralleled the occurrence of intracerebral hemorrhage (online-only, Supplemental Data, Appendix VII).
Participants with subdural hematomas were older (P⬍0.001),
were assigned to warfarin (P⫽0.001), more often used aspirin
during follow-up (P⫽0.001), and had reduced creatinine
Table 5. Mortality Rates of Intracranial Hemorrhages by
Treatment Arm and Site*
Mortality Rates†
Warfarin,
% (n/n)
Dabigatran
150 mg,
% (n/n)
Dabigatran
110 mg,
% (n/n)
All intracranial
36% (32/90)
35% (13/37)
41% (11/27)
Intracerebral
41% (19/46)
64% (7/11)
64% (9/14)
45% (19/42)
64% (7/11)
70% (7/10)
0% (0/4)
0% (0/0)
50% (2/4)
28% (10/36)
21% (5/24)
20% (2/10)
Spontaneous†
Traumatic
Subdural
Spontaneous
25% (5/20)
14% (2/14)
20% (1/5)
Traumatic
31% (5/16)
30% (3/10)
20% (1/5)
38% (3/8)
50% (1/2)
0% (0/3)
75% (3/4)
100% (1/1)
0% (0/1)
0% (0/4)
0% (0/1)
0% (0/2)
Subarachnoid
Spontaneous
Traumatic
*Intention-to-treat analysis; see methods for criteria for spontaneous vs
traumatic. Patients with traumatic intracranial hemorrhages in whom other
noncentral nervous system consequences of trauma clearly led to death are not
counted as fatal.
†There were no statistically significant differences comparing warfarin with
either dose of dabigatran for any site; for spontaneous intracerebral hemorrhage, for dabigatran 110 mg vs warfarin: relative risk, 1.6; P⫽0.76; for
dabigatran 150 mg vs warfarin: relative risk, 1.4; P⫽0.28.
clearance (P⬍0.001) compared with patients without intracranial hemorrhage (Table 2). A history of falls before study
entry was not significantly predictive (Table 2); only age was
an independent predictor of developing subdural hematomas
for patients assigned to warfarin (RR, 1.05; P⫽0.04),
whereas assignment to the higher dabigatran dosage (RR, 2.4;
P⫽0.02) and male sex (RR, 2.5; P⫽0.03) independently
predicted subdural hematomas among dabigatran-assigned
patients (Table 3).
The rate of subdural hematoma was 0.31% per year (n⫽36)
among those assigned to warfarin versus 0.20% per year for
those assigned to dabigatran 150 mg (n⫽24; RR, 0.65;
P⫽0.10) and 0.08% per year for dabigatran 110 mg (n⫽10;
RR, 0.27; P⬍0.001; Table 4). The rate of subdural hematomas was significantly higher with dabigatran 150 mg compared with the 110 mg dosage (RR, 2.4; P⫽0.02; Table 4).
Fatal subdural bleeding occurred in 10 patients assigned to
warfarin versus 5 patients and 2 patients to dabigatran 150 mg
and 110 mg, respectively (P⬍0.05 for dabigatran 110 mg
compared with warfarin).
Traumatic Intracranial Hemorrhages
Of 46 traumatic intracranial hemorrhages, 67% were subdural
hematomas (Table 1). Significantly fewer traumatic intracranial hemorrhages occurred among those assigned to either
dosage of dabigatran (11 patients for both dosages) compared
with warfarin (24 patients; (P⬍0.05 for both dabigatran
dosages versus warfarin; Table 4). Fatal traumatic intracranial
hemorrhages occurred in 5 patients, 3 patients, and 3 patients
assigned to warfarin, dabigatran 150 mg, and dabigatran 110
mg, respectively (Table 5).
Discussion
The major findings of these analyses are the similar
frequencies of spontaneous intracerebral hemorrhage and
subdural hematoma in warfarin-assigned patients, the importance of concomitant aspirin use as a risk factor for
Downloaded from http://stroke.ahajournals.org/ by guest on September 9, 2014
1516
Stroke
June 2012
spontaneous intracerebral hemorrhage, and the substantially lower rates at all sites of intracranial hemorrhage and
of absolute mortality rates because of intracranial bleeding
with dabigatran compared with high-quality warfarin anticoagulation. In addition, this first analysis of the role of
trauma in intracranial hemorrhage in dabigatran-treated
patients reveals significantly lower absolute rates compared with patients assigned to warfarin.
Intracerebral hemorrhage is the most devastating complication of anticoagulation, with mortality rates exceeding 50%
in most studies (52% in RE-LY).1,9 –11 This highly lethal
stroke subtype cannot be considered equivalent to ischemic
stroke when assessing clinical trial outcomes.9,12 Absolute
rates of intracerebral hemorrhage during warfarin anticoagulation of atrial fibrillation patients in recent studies
ranged from 0.3% per year to 0.6% per year (0.39% per
year in RE-LY).2,3,9,12,13 Consequently, the lower intracranial hemorrhage rates during anticoagulation with dabigatran compared with warfarin are not explained by unduly
high rates during warfarin anticoagulation, but rather by
low rates with dabigatran that approximate the rate in
nonanticoagulated atrial fibrillation patients.14 Concomitant aspirin use has been associated with intracranial
hemorrhage during warfarin anticoagulation in most,13–16
but not all,17 previous studies and was confirmed as an
independent risk factor here.
Subdural hematomas are collections of blood between the
dura and leptomeninges, most often seen in older people and
resulting from a tear in the veins bridging the meninges.
Consequently, all subdural hematomas are theoretically traumatic, although the trauma causing the dural tear is often
trivial and subclinical. In previous studies of older patients
taking warfarin, subdural hematomas made up about 30% of
intracranial hemorrhages with absolute rates between 0.1% to
0.3% per year and associated mortality rates averaging 20%
to 30%.1–3 The rate of subdural hematoma in RE-LY was
0.31% per year with warfarin and was significantly lower
among those assigned dabigatran 110 mg (RR, 0.27; P⬍0.001),
but not for those given dabigatran 150 mg (RR, 0.65;
P⫽0.10; Table 4). Predisposition to falling was found to be
an independent risk factor for intracranial hemorrhage in a
large study of Medicare beneficiaries with atrial fibrillation,11
but a history of falling was not independently predictive
among RE-LY participants.
All sites of intracranial hemorrhage were less frequent in
patients assigned to dabigatran compared with warfarin. It has
been hypothesized that warfarin interferes with tissue factor
VIIa-mediated thrombosis that may be especially important
for hemostasis within the brain, whereas novel oral anticoagulants do not because of their more selective mechanisms of
action. Any explanation for the lower rates of intracranial
hemorrhage seen with dabigatran must account for reduced
rates associated with all sites of intracranial hemorrhage and
with traumatic versus atraumatic hemorrhages.
There is concern that patients with intracranial hemorrhages during treatment with dabigatran could have a worse
prognosis than could those with warfarin because of the
absence of a proven treatment to reverse emergently the
antithrombotic effect. Mortality from intracranial hemorrhage
was not increased in dabigatran-treated patients compared
with those given warfarin (Table 5). This observation, coupled with the substantially lower absolute rates of intracranial
hemorrhage with dabigatran, explains why the likelihood of
dying from intracranial bleeding is significantly lower
(P⬍0.01) during anticoagulation with dabigatran versus warfarin. Although no intervention has convincingly been shown
to reduce the mortality of warfarin-associated intracranial
bleeding, treatments differ worldwide,18 and it is unclear
whether these results of the international RE-LY study apply
to centers in which reversal of warfarin anticoagulation is
aggressively undertaken in this setting.
In summary, in this cohort of older atrial fibrillation patients
with well-controlled blood pressure, the clinical spectrum of
intracranial hemorrhages was similar for patients given warfarin versus dabigatran, but with substantially lower absolute
rates of all sites of intracranial hemorrhage and of traumatic
intracranial hemorrhage with dabigatran. Almost half of
intracranial hemorrhages were subdural hematomas, which
were frequently associated with trauma. Fatal intracranial
hemorrhages were substantially less frequent with dabigatran
than with warfarin. Aspirin use independently predicted
spontaneous intracerebral hemorrhage with warfarin. The
underlying mechanism(s) accounting for the low risk of all
sites of intracranial bleeding with dabigatran and other novel
oral anticoagulants are critical to understand, but remain to be
fully elucidated.
Sources of Funding
This study was funded by Boehringer Ingelheim.
Disclosures
P.A.R. is an employee of Boehringer Ingelheim, and all other
coauthors have served as consultants, except S.Ya.
References
1. Fang MC, Go AS, Chang Y, Hylek EM, Henault LE, Jensvold NG, et al.
Death and disability from warfarin-associated intracranial and
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2. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al, the
ROCKET Steering Committee for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med.
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3. Granger CB, Alexander JH, McMurray JJV, Lopes RD, Hylek EM,
Hanna M, et al, for the ARISTOTLE Committees and Investigators.
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et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl
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with atrial fibrillation. N Engl J Med. 2009;360:2066 –2078.
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al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial Fibrillation Clopidogrel Trial with Irbesartan for
prevention of Vascular Events (ACTIVE W). Lancet. 2006;367:
1903–1912.
7. Ezekowitz MD, Connolly SJ, Parekh A, Reilly PA, Varrone J, Wang S,
et al. Rationale and design of RE-LY: randomized evaluation of
long-term anticoagulant therapy, warfarin, compared with dabigatran. Am
Heart J. 2009;157:805– 810.
8. Connolly SJ, Ezekowitz MD, Yusuf S, Wallentin L. Newly identified
events in the RE-LY trial. N Engl J Med. 2010;363:1875–1876.
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9. Singer DE, Chang Y, Fang MC, Borowsky LH, Pomernacki NK,
Udaltsova N, et al. The net clinical benefit of warfarin anticoagulation in
atrial fibrillation. Ann Intern Med. 2009;151:297–305.
10. Huhtakangas J, Tetri S, Juvela S, Saloheimo P, Bode MK, Hillbom M.
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MW. Incidence of intracranial hemorrhage in patients with atrial fibrillation who are prone to fall. Am J Med. 2005;118:612– 617.
12. Connolly SJ, Eikelboom J, Ng J, Hirsh J, Yusuf S, Pogue J, et al.
Weighted net clinical benefit of addition of clopidogrel to aspirin in
patients with atrial fibrillation unsuitable for a vitamin K antagonist. Ann
Intern Med. 2011;155:579 –586.
13. Hansen ML, Sorensen R, Clausen MT, Fog-Petersen ML, Raunso J,
Gadsboll N, et al. Risk of bleeding with single, dual, or triple therapy with
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26
Stroke 日本語版 Vol. 7, No. 2
Abstract
ワルファリンまたはダビガトランを用いた抗凝固療法中の心
房細動患者に発症する頭蓋内出血 — RE-LY 試験
Intracranial Hemorrhage in Atrial Fibrillation Patients During Anticoagulation With Warfarin
or Dabigatran ― The RE-LY Trial
Robert G. Hart,MD1; Hans-Christoph Diener, MD2; Sean Yang, MSc1; Stuart J. Connolly, MD1; Lars
Wallentin, MD3; Paul A. Reilly, PhD4; Michael D. Ezekowitz, DPhil5; Salim Yusuf, DPhil1
1 Population Health Research Institute, McMster University and Hamilton Health Sciences, Hamilton, Ontario, Canada; 2 Department of
Neurology, University Duisburg-Essen, Essen, Germany; 3 Uppsala Clinical Research Centre, Uppsala University, Uppsala, Sweden; 4 Boehringer
Ingelheim, Ridgefield, CT; 5 Lankenau Institute for Medical Research, Wynnewood, PA.
背景および目的：頭蓋内出血は抗凝固療法の最も深刻な合
併症である。ダビガトランまたはワルファリンによって発
生する頭蓋内出血の様々な部位に関連した転帰は明らかに
なっていない。
方法：Randomized Evaluation of Long-term anticoagulant
therapY（ RE-LY ）試験に参加した心房細動患者 18,113 例
を，用量調整ワルファリン（ 目標国際標準化比［ INR ］
：2
～ 3 ）またはダビガトラン（ 150 mg または 110 mg，いずれ
も 1 日 2 回 ）に割り付け，解析した。
結 果： 平 均 2.0 年 の 追 跡 期 間 中，153 例 の 被 験 者 に 154
件の頭蓋内出血が発生した。内訳は 46％が脳内（ 死亡率
49％），45％が硬膜下（ 死亡率 24％）
，および 8％がくも
膜下（ 死亡率 31％）であった。ワルファリン，ダビガト
ラン 150 mg およびダビガトラン 110 mg に割り付けられ
た患者の 1 年あたりの頭蓋内出血の発生率は，それぞれ
0.76％，0.31％，および 0.23％であった（ いずれかの用量
のダビガトラン 対 ワルファリンについて p ＜ 0.001 ）
。ダ
ビガトラン 150 mg または 110 mg に割り付けられた患者
の致死的頭蓋内出血の発生数は（ それぞれ 13 例および 11
例）
，ワルファリンに割り付けられた患者よりも少なかっ
た（ 32 例，両用量について p ＜ 0.01 ）。ダビガトラン群の
患者では，外傷性頭蓋内出血の発生数（ 各用量で 11 例）が
ワルファリン群よりも少なかった（ 24 例，ダビガトランの
両用量 対 ワルファリンについて p ＜ 0.05 ）
。頭蓋内出血
の独立予測因子は，ワルファリン群への割り付け（相対リ
スク＝ 2.9，p ＜ 0.001 ）
，アスピリンの使用（相対リスク＝
1.6，p ＝ 0.01 ）
，年齢
（ 1 歳あたりの相対リスク＝ 1.1，p ＜
0.001 ）および脳卒中 / 一過性脳虚血発作の既往（相対リス
ク＝ 1.8，p ＝ 0.001 ）
であった。
結論：頭蓋内出血の臨床スペクトルは，ワルファリンおよ
びダビガトランを投与した患者で同様であった。すべての
部位，また致死的および外傷性両方の頭蓋内出血の絶対発
生率は，ワルファリン群よりもダビガトラン群で低かった。
アスピリンの併用は，頭蓋内出血の最も重大で，修正可能
な独立危険因子であった。
Stroke 2012; 43: 1511-1517
表 4 割り付けた治療別の頭蓋内出血の部位と発現率 *
ダビガトラン ダビガトラン
ワルファリン
150 mg
110 mg
例数 / 率
例数 / 率
例数 / 率
（％ / 年） （％ / 年） （％ / 年）
ダビガトラン 150 mg 対
ワルファリン
RR（95％ CI）
p値
ダビガトラン 110 mg 対
ワルファリン
RR（95％ CI）
p値
ダビガトラン 150 mg 対
110 mg
RR（ 95％ CI ）
p値
頭蓋内全体（ 154 例） 90/0.76
37/0.31
27/0.23
0.40（0.27 〜 0.59）＜ 0.001
0.30（0.19 〜 0.45）＜ 0.001
1.4（0.83 〜 2.2 ） NS
脳内（ 71 例 ）
46/0.39
11/0.09
14/0.12
0.23（0.12 〜 0.45）＜ 0.001
0.30（0.16 〜 0.54）＜ 0.001
0.78（0.35 〜 1.7 ） NS
特発性
42/0.36
11/0.09
10/0.08
0.26（0.13 〜 0.50）＜ 0.001
0.23（0.12 〜 0.47）＜ 0.001
1.1（0.46 〜 2.6 ） NS
外傷性
4/0.03
硬膜下（ 70 例 ）
36/0.31
0/0.0
24/0.20
4/0.03
10/0.08
0.0
NS
0.65（0.39 〜 1.1）
0.10
0.99
NS
0.27（0.12 〜 0.55）＜ 0.001
0.0
NS
2.4（1.1 〜 5.0 ）
特発性
20/0.17
14/0.12
5/0.04
0.68
NS
0.25（0.09 〜 0.66）
0.005
2.8（1.0 〜 7.7 ）
外傷性
16/0.14
10/0.08
5/0.04
0.61
NS
0.31（0.11 〜 0.84）
0.02
2.0（0.68 〜 5.8 ） NS
NS
くも膜下（ 13 例）
8/0.06
2/0.02
3/0.03
0.24（0.05 〜 1.2）
0.07
0.37
NS
0.66（0.11 〜 4.0 ） NS
特発性
4/0.03
1/0.01
1/0.01
0.24
NS
0.24
NS
0.99（0.06 〜 16 ） NS
外傷性
4/0.03
1/0.01
2/0.02
0.25
NS
0.50
NS
0.50（0.04 〜 5.5 ） NS
RR：相対リスク，NS：統計学的有意差なし（p ＞ 0.05）。
* 特発性 対 外傷性の基準については，当論文の方法のセクションを参照。比率は，特定のタイプの頭蓋内出血のある患者を分母とし，intention-to-treat パラ
ダイムによって算出した。on-treatment 解析の結果は同様であり，オンラインのみの補足データの補遺 IV に収載されている。
SUPPLEMENTAL MATERIALS
Note: Appendix V was on revised 30 September 2013
Appendix I. Features of patients with intracranial bleeding according to treatment
assignment
Table 1. Features of patients assigned to warfarin with intracranial hemorrhage
Features
No
intracranial
hemorrhage
(n = 5932)
Any
intracranial
hemorrhage
(n = 90)
p^
Mean age (yrs)
Men (%)
White (%)
Hypertension (%)
Diabetes (%)
Heart failure (%)
Coronary artery disease (%)
Prior stroke/TIA (%)
Paroxysmal AF (%)
Prior VKA use (%)+
Systolic blood pressure at
entry (mean) mmHg
Tobacco smoking (%)
Alcohol consumption (%)
History of falls (%)
% time in therapeutic range
(mean)
% time INR >3.0 (mean)
Aspirin use prior to
hemorrhage (%)
Mean creatinine clearance
72
63%
70%
79%
23%
32%
28%
20%
34%
49%
131
74
61%
60%
83%
24%
22%
27%
33%
37%
53%
132
50%
33%
11%
65%
p^^
Subdural
hematoma
(n = 36)
p^^^
<0.001
NS
0.04
NS
NS
0.04
NS
0.001
NS
NS
NS
Spontaneous
intracerebral
hemorrhage*
(n = 42)
74
55%
57%
86%
31%
17%
21%
43%
31%
48%
133
NS
NS
NS
NS
NS
0.03
NS
<0.001
NS
NS
NS
74
64%
61%
81%
17%
29%
33%
25%
44%
56%
133
0.02
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
49%
29%
17%
60%
NS
NS
NS
NS
45%
31%
12%
61%
NS
NS
NS
NS
56%
31%
14%
59%
NS
NS
NS
NS
13%
32%#
17%
43%
NS
0.02
16%
48%
NS
0.03
18%
39%
NS
NS
73
63
<0.001
63
<0.001
64
0.008
(ml/min)(Cockcroft-Gault)
TIA = transient ischemic attack; BP = blood pressure; AF = atrial fibrillation; VKA = vitamin K antagonist;
NS = not statistically significant (p>0.05).
*Traumatic intracerebral hemorrhages are not included.
^ Comparing no intracranial hemorrhage to any intracranial hemorrhage
^^ Comparing spontaneous intracerebral hemorrhage to no intracranial hemorrhage
^^^ Comparing subdural hematomas to no intracranial hemorrhage
+Total life-time use >62 days
# For participants without intracranial hemorrhages, the fraction using aspirin at any follow-up visit prior to
the mean time to intracranial hemorrhage is considered.
1
Table 2. Features of patients assigned to dabigatran (either dosage) with intracranial
hemorrhage
Features
Mean age (yrs)
Men (%)
White (%)
Hypertension (%)
Diabetes (%)
Heart failure (%)
Coronary artery disease (%)
Prior stroke/TIA (%)
Paroxysmal AF (%)
Prior VKA use (%)+
Systolic blood pressure at
entry (mean) mmHg
Tobacco smoking (%)
Alcohol consumption
History of falls (%)
Higher dabigatran dose (%)
Aspirin use prior to
hemorrhage (%)
Mean creatinine clearance
No
intracranial
hemorrhage
(n = 12028)
Any
intracranial
hemorrhage
(n = 63)
p^
71
64%
70%
79%
23%
32%
28%
20%
32%
50%
131
75
71%
68%
84%
27%
25%
29%
27%
35%
52%
130
51%
33%
11%
50%
31%#
73
p^^
Subdural
hematomas
(n = 34)
p^^^
<0.001
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
Spontaneous
intracerebral
hemorrhages*
(n = 21)
75
52%
71%
86%
19%
24%
14%
33%
24%
57%
133
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
76
79%
70%
82%
30%
21%
36%
30%
39%
52%
126
0.001
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
60%
25%
14%
59%
40%
NS
NS
NS
NS
NS
52%
29%
5%
52%
38%
NS
NS
NS
NS
61%
21%
21%
71%
38%
NS
NS
0.07
0.02
NS
62
<0.001
62
0.02
62
0.007
NS
(ml/min)(Cockcroft-Gault)
TIA = transient ischemic attack; BP = blood pressure; AF = atrial fibrillation; VKA = vitamin K antagonist;
NS = not statistically significant (p>0.05).
* Traumatic intracerebral hemorrhages are not included.
^ Comparing no intracranial hemorrhage to any intracranial hemorrhage
^^ Comparing spontaneous intracerebral hemorrhage to no intracranial hemorrhage
^^^ Comparing subdural hematomas to no intracranial hemorrhage
+Total life-time use >62 days.
# For participants without intracranial hemorrhages, the fraction using aspirin at any follow-up visit prior to
the mean time to intracranial hemorrhage is considered.
2
Table 3. Features of patients with intracranial hemorrhage assigned to warfarin vs.
dabigatran*
Features
Warfarin-assigned
(n=90)
Dabigatran-assigned^
(n = 63)
Mean age (yrs)
74
75
Men (%)
61%
71%
White (%)
60%
68%
Hypertension (%)
83%
84%
Diabetes (%)
24%
27%
Heart failure (%)
22%
25%
Coronary artery disease (%)
27%
29%
Prior stroke/TIA (%)
33%
27%
Paroxysmal AF (%)
37%
35%
Prior VKA use (%)+
53%
52%
Systolic blood pressure at entry (mean) mmHg
132
130
Tobacco smoking (%)
49%
60%
Alcohol consumption
29%
25%
History of falls (%)
17%
14%
Aspirin use prior to hemorrhage (%)
43%
40%
Mean creatinine clearance (ml/min)(Cockcroft-Gault)
63
62
TIA = transient ischemic attack; BP = blood pressure; AF = atrial fibrillation; VKA = vitamin K antagonist;
* There were no statistically significant differences for any feature (all p values >0.05)
^ Both dosages.
3
Appendix II. Features of patients with subdural hematomas
Features
Mean age (yrs)
Men (%)
White (%)
Hypertension (%)
Diabetes (%)
Heart failure (%)
Coronary artery disease (%)
Prior stroke/TIA (%)
Paroxysmal AF (%)
Prior VKA use (%)+
Systolic blood pressure at
entry (mean) mmHg
Tobacco smoking (%)
Alcohol consumption
History of falls (%)
Aspirin use at first postrandomization follow-up (%)
Mean CHADS2 score
Mean creat clearance
Spontaneous
subdural
(n = 39)
75
67%
59%
82%
18%
23%
28%
23%
39%
56%
131
Traumatic
subdural
(n = 31)
75
77%
71%
81%
32%
26%
42%
32%
48%
48%
129
P^
Warfarin- Dabigatranassigned
assigned*
(n = 36)
(n = 34)
74
76
64%
79%
61%
68%
81%
82%
17%
32%
28%
21%
33%
35%
25%
29%
44%
41%
56%
50%
133
128
P^^
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
51%
33%
18%
54%
68%
16%
16%
52%
NS
NS
NS
NS
56%
31%
14%
47%
62%
21%
21%
59%
NS
NS
NS
NS
2.2
65
2.6
60
NS
NS
2.3
64
2.5
61
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
(ml/min)(Cockcroft-Gault)
TIA = transient ischemic attack; BP = blood pressure; AF = atrial fibrillation; VKA = vitamin K antagonist;
spont ICH = spontaneous intracerebral hemorrhage.
* Both dosages of dabigatran combined.
^Comparing patients with spontaneous to traumatic subdural hematomas
^^Comparing warfarin-assigned patients with subdural hematomas to those assigned dabigatran.
4
Appendix III. Features independently predictive of intracranial hemorrhage: ontreatment analysis*
All participants
All intracranial hemorrhages (n=130)
Spontaneous intracerebral bleeds (n=53)
Subdural hematomas (n=59)
Warfarin-assigned
All intracranial hemorrhages (n=84)
Spontaneous intracerebral bleeds (n=39)
Subdural hematomas (n=34)
Dabigatran-assigned (both dosages)
All intracranial hemorrhages (n=46)
Spontaneous intracerebral bleeds (n=14)
Subdural hematomas (n=25)
Feature
Relative
risk
p-value
age (per year)
prior stroke/TIA
assigned warfarin
aspirin use
age (per year)
prior stroke/TIA
assigned warfarin
age (per year)
assigned warfarin
1.1
1.6
3.8
1.5
1.05
2.7
5.7
1.1
2.7
<0.001
0.02
<0.001
0.02
0.01
<0.001
<0.001
0.003
<0.001
age (per year)
prior stroke/TIA
TTR
age (per year)
prior stroke/TIA
age
1.05
2.0
0.99
1.04
3.5
1.05
0.001
0.004
0.03
0.04
<0.001
0.04
age (per year)
male
none
age (per year)
male
1.1
2.2
1.1
3.4
0.001
0.03
0.02
0.03
TTR = time in therapeutic range (INR 2-3); RR = relative risk; TIA = transient ischemic attack.
*Events and follow-up censored after assigned treatment was withdrawn for >30 days. The models
included variables that had p-values of <0.1 by univariate analysis (Table 2, Appendix 1) except for
creatinine clearance. When creatinine clearance was included, age and prior stroke/TIA were no
longer significant, and creatinine clearance (per increment by 10 mL/min) was significantly predictive
of all intracranial hemorrhage (RR=0.90, p=0.03) in all participants and of all intracranial hemorrhage
(RR=0.87, p=0.03) in warfarin-assigned patients, but not in dabigatran-assigned patients.
5
Appendix IV. Sites and rates of intracranial hemorrhage: On-treatment*
Warfarin
N / rate
(%/yr)
Dabigatran
150 mg
N / rate
(%/yr)
Dabigatran 150 mg
vs. Warfarin
RR (95%CI)
p
Dabigatran
110 mg
N / rate
(%/yr)
Dabigatran 110 mg
vs. Warfarin
RR (95%CI)
p
All intracranial (n=130)
84 / 0.71
25 / 0.21
0.29(0.19-0.45) <0.001
21/0.18
0.25(0.15-0.40)
Intracerebral (n=60)
42/0.36
8/0.07
0.19(0.09-0.40) <0.001
10/0.08
0.23(0.12-0.47)
- spontaneous
39/0.33
8/0.07
0.20(0.09-0.43) <0.001
6/0.05
0.15(0.06-0.36)
- traumatic
3/0.03
0/0
0
NS
4/0.03
1.32(0.30-5.92)
Subdural (n=59)
34/0.29
17/0.14
0.49(0.27-0.87)
0.02
8/0.07
0.23(0.11-0.50)
- spontaneous
20/0.17
9/0.07
0.44(0.20-0.97)
0.04
5/0.04
0.25(0.09-0.66)
- traumatic
14/0.12
8/0.07
0.56(0.23-1.33)
NS
3/0.03
0.21(0.06-0.74)
Subarachnoid (n=11)
8/0.07
0
0
NS
3/0.03
0.37(0.10-1.39)
- spontaneous
4/0.03
0
0
NS
1/0.01
0.24(0.03-2.19)
- traumatic
4/0.03
0
0
NS
2/0.02
0.50(0.09-2.71)
* On-treatment results with events and follow-up censored after assigned treatment was withdrawn for >30
days.See methods for criteria for spontaneous vs. traumatic. Rates calculated using the denominator of
exposure for the specific type of intracranial hemorrhage.
^ relative risk and p-value comparing dabigatran 150 mg to warfarin.
^^ relative risk and p-value comparing dabigatran 110 mg to warfarin.
6
<0.001
<0.001
<0.001
NS
<0.001
0.005
0.01
NS
NS
NS
Appendix V. Relative risks of intracranial hemorrhage comparing dabigatran with
warfarin in subgroups defined by independent predictors.
Revised and corrected 30 September 2013: data for creatinine clearance.
7
Dabig 110mg
Dabig 150mg
Warf
N
E
Rate
/100
PYrs
Age <75
3666
10
0.14
3610
18
0.25
3599
43
0.61
0.22
0.11-0.45
0.0000
Age >=75
2349
16
0.35
2466
19
0.40
2423
47
1.00
0.35
0.20-0.61
0.0002
White
4208
17
0.20
4268
26
0.30
4203
54
0.64
0.31
0.18-0.54
0.0000
Non white
1806
9
0.26
1808
11
0.31
1819
36
1.05
0.24
0.12-0.51
0.0002
Creatinine clearance<60
2161
18
0.44
2187
17
0.40
2129
42
1.04
0.41
0.24-0.72
0.0017
Creatinine clearance>=60
3796
8
0.10
3842
20
0.26
3836
48
0.63
0.17
0.08-0.35
0.0000
ASA use
1933
8
0.21
1877
17
0.46
1915
39
1.06
0.20
0.09-0.43
0.0000
No ASA use
4082
18
0.22
4199
20
0.24
4107
51
0.63
0.35
0.20-0.60
0.0001
Prior Stroke/TIA
1195
6
0.25
1233
11
0.45
1195
30
1.28
0.20
0.08-0.47
0.0003
No Prior Stroke/TIA
4819
20
0.21
4843
26
0.27
4827
60
0.63
0.33
0.20-0.55
0.0000
Event
N
E
Rate
/100
PYrs
N
D 110 vs. W
E
Rate
/100
PYrs
RR
95% CI
p
8
D 150 vs. W
Int P
0.3462
0.6072
0.0521
0.2457
0.3085
RR
95% CI
p
0.41
0.24-0.71
0.0014
0.39
0.23-0.67
0.0006
0.47
0.30-0.75
0.0016
0.29
0.15-0.57
0.0004
0.39
0.22-0.68
0.0009
0.41
0.24-0.69
0.0009
0.44
0.25-0.77
0.0045
0.38
0.23-0.63
0.0002
0.35
0.17-0.70
0.0028
0.43
0.27-0.68
0.0003
Int P
0.9181
0.2677
0.8805
0.7146
0.6196
Appendix VI. Features of patients with spontaneous intracerebral hemorrhage according
to the major site of bleeding (all treatment arms)*
Features
Mean age (yrs)
Men (%)
White (%)
Hypertension (%)
Diabetes (%)
Heart failure (%)
Coronary artery disease (%)
Prior stroke/TIA (%)
Paroxysmal AF (%)
Systolic blood pressure at entry
(mean) mmHg
Tobacco smoking (%)
Alcohol use (%)
Assigned to warfarin (%)
Mean creatinine clearance
Basal ganglia/
thalamus
N = 26
Lobar/
cortex
N=23
p
72
42%
54%
89%
42%
8%
15%
39%
19%
131
76
70%
61%
83%
13%
22%
17%
35%
39%
136
0.04
NS
NS
NS
0.02
NS
NS
NS
NS
NS
46%
27%
73%
62
52%
22%
57%
66
NS
NS
NS
NS
(ml/min)(Cockcroft-Gault)
Surgical treatment^ (%)
8%
9%
NS
Outcome (%)
NS
- full recovery
4%
8%
- survived with deficit
39%
27%
- fatal
39%
50%
- uncertain
17%
15%
Treatment assignment
NS
- warfarin
19
13
- dabigatran (either dosage)
7
10
TIA = transient ischemic attack; BP = blood pressure; AF = atrial fibrillation; NS = not statistically
significant (p>0.05).
* The site of intracranial bleeding could not be determined with confidence for six patients, who are
excluded from the table. Of 39 spontaneous intracerebral hemorrhages in warfarin-assigned patients for
which the location could be determined, four (10%) were cerebellar; 0 of 19 were cerebellar among those
assigned to dabigatran.
^Includes craniotomy or ventriculostomy.
9
Appendix VII. Cumulative rated of (a) spontaneous intracerebral hemorrhage by assigned
treatment, (b) subdural hematoma by assigned treatment, and (c) spontaneous intracrerebral
hemorrhages and subdural hematoma.
Year 0.5
5901
5961
5897
1.0
5774
5825
5769
1.5
4669
4741
4649
2.0
3010
3086
2951
2.5
1422
1456
1349
0.010
# at Risk
D110 6015
D150 6076
W
6022
Warfarin
0.005
Cumulative Hazard Rates
0.015
Time to Spontaneous intracerebral hemorrhage
Dabigatran150
0.0
Dabigatran110
0
0.5
1.0
1.5
2.0
2.5
Years of Follow-up
Year 0.5
5901
5956
5897
1.0
5772
5819
5767
1.5
4670
4736
4644
2.0
3008
3080
2944
2.5
1421
1451
1351
0.010
# at Risk
D110 6015
D150 6076
W
6022
0.005
Warfarin
Dabigatran150
Dabigatran110
0.0
Cumulative Hazard Rates
0.015
Time to Subdural hematomas
0
0.5
1.0
1.5
Years of Follow-up
10
2.0
2.5
Year 0.5
17759
17754
1.0
17368
17358
1.5
14059
14050
2.0
9047
9032
2.5
4227
4223
0.005
0.010
# at Risk
Spontaneous 18113
Subdural
18113
Subdural hematomas
Spontaneous ICH
0.0
Cumulative Hazard Rates
0.015
Time to Spontaneous intracerebral hemorrhage and Subdural hematomas
0
0.5
1.0
1.5
Years of Follow-up
11
2.0
2.5
34 Stroke 한국어판 Vol. 5, No. 3
Abstract 13
심방세동 환자에서 와파린과 Dabigatran
항응고요법 중 두개뇌출혈
RE-LY 연구
Intracranial Hemorrhage in Atrial Fibrillation Patients During Anticoagulation
With Warfarin or Dabigatran
The RE-LY Trial
Robert G. Hart, MD; Hans-Christoph Diener, MD; Sean Yang, MSc; Stuart J. Connolly, MD; Lars Wallentin, MD;
Paul A. Reilly, PhD; Michael D. Ezekowitz, DPhil; Salim Yusuf, DPhil
(Stroke. 2012;43:1511-1517.)
Key Words: atrial fibrillation ■ intracranial hemorrhage ■ intracerebral hemorrhage ■ warfarin ■ anticoagulation
■ subdural hematoma ■ dabigatran
배경과 목적
두개내출혈은 항응고요법의 가장 심각한 합병증이다. 와파린
및 dabigatran 사용 중 발생한 두개내출혈의 부위와 연관된
예후는 아직까지 밝혀져 있지 않다.
방법
Randomized Evaluation of Long-term anticoagulant
therapY (RE-LY) 연구에서 용량 조절 와파린(목표 INR, 2~
3)군과 dabigatran (150 mg or 110 mg, 하루 두 번)으로 할당
된 18,113명의 심방세동 환자들에 대한 분석을 하였다.
결과
2년의 추적관찰 기간 동안 153명의 환자에서 154건의 두개내
출혈이 발생하였다. 이 중 46%는 뇌실질내출혈(49% 사망률),
45%는 경막하출혈(24% 사망률)이었으며, 8%는 거미막하출혈
(31% 사망률)이었다. 두개내출혈의 연간발생률은 와파린군에
서 0.76%, dabigatran 150 mg군에서 0.31%였으며 110 mg
군에서는 0.23%였다(dabigatran 대 와파린, P＜0.001). 치명
적인 두개내출혈은 dabigatran 150 mg군에서는 13명, 110
mg군에서는 11명인 반면, 와파린군에서는 32명으로 조사되었
다(P＜0.01). 외상성 두개내출혈도 dabigatran의 두 용량군에
서는 각각 11명이 발생하였고, 와파린군에서는 24명이 발생하
였다(dabigatran 대 와파린, P＜0.05). 두개내출혈의 독립적
인 예측인자들은 와파린군 배정(RR 2.9; P＜0.001), 아스피린
사용(RR 1.6; P=0.01), 나이(RR 1.1/년; P＜0.001) 및 뇌졸중
/일과성허혈발작 병력(위험도 1.8; P=0.001)이었다.
결론
와파린과 dabigatran을 복용한 환자들에서 두개내출혈의 임
상적 스팩트럼은 유사하였다. 치명적, 외상성 두개내출혈 및
모든 부위에서의 두개내출혈의 절대적 발생률은 dabigatran
군보다 와파린군에서 높았다. 아스피린을 함께 사용하는 것이
두개내출혈의 발생에 있어 가장 중요한 변경이 가능한 위험인
자임이 확인되었다.
35