ORIGINAL CONTRIBUTION

SFMV fb 74 / 670.0810

Restarting Anticoagulation Therapy After

Warfarin-Associated Intracerebral Hemorrhage
Daniel O. Claassen, MD; Noojan Kazemi, MBBS; Alexander Y. Zubkov, MD, PhD; Eelco F. M. Wijdicks, MD;
Alejandro A. Rabinstein, MD

Background: Reinitiating warfarin sodium therapy in
a patient with a recent warfarin-related intracerebral hem-
orrhage (WAICH) is a difficult clinical decision. There-
fore, it is important to assess the outcome of resump-
tion or discontinuation of warfarin therapy after WAICH.
Objective: To compare patients who survived an epi-
sode of WAICH and restarted warfarin therapy with a
group of WAICH patients who did not resume warfarin
therapy.
Design, Setting, and Patients: We conducted a fol-
low-up study from November 1, 2001, through Decem-
ber 31, 2005, in a cohort from a single center. Long-
term outcome was assessed at last clinical follow-up or
via questionnaire.
Main Outcome Measures: Recurrent WAICH and
thromboembolic events.
Results: Fifty-two patients were discharged from the hos-
pital after a diagnosis of WAICH. Four patients were lost
to follow-up. Mean follow-up among all patients was 43
(range, 1-108) months. Of the 23 patients who restarted
warfarin therapy, 1 had a recurrent nontraumatic WAICH,
2 had traumatic intracerebral hemorrhages, and 2 had
major extracranial hemorrhages. Of the 25 patients who
did not restart warfarin therapy, 3 had a thromboem-
bolic stroke, 1 had a pulmonary embolus, and 1 had a
distal arterial embolus.
Conclusions: Restarting warfarin therapy in patients with
a recent WAICH is associated with a low risk of recur-
rence, but patients are subjected to known, substantial
risks of warfarin use. Withholding warfarin therapy is as-
sociated with a risk of thromboembolization.
Arch Neurol. 2008;65(10):1313-1318

Author Affiliations:
Department of Neurology, Mayo
Clinic, Rochester, Minnesota.
T
HE USE OF WARFARIN SO -
dium is rapidly increasing
with the aging of the gen-
eral population.1-3 Warfa-
rin prevents thromboem-
bolic events in patients with mechanical
valve prostheses,4 atrial fibrillation,5 or ve-
nous thromboembolism, but its use in-
creases the risk of intracerebral hemor-
rhage (ICH). 6 - 8 As the incidence of
warfarin-associated ICH (WAICH) also in-
creases,9 the question of whether to re-
start warfarin therapy after WAICH is be-
coming more common in practice.
Reinitiating warfarin therapy in a pa-
tient with a recent WAICH is a difficult
proposition, and the assessment of risks is
a pertinent question for any physician.
Competing risks include the risk of recur-
rent ICH if warfarin therapy is restarted vs
the risk of recurrent thromboembolism
without warfarin therapy. In addition, pa-
tients with residual neurological deficits
from WAICH could be at increased risk of
traumatic bleeding from falls. Very lim-
ited clinical data describe the long-term risk
of recurrent ICH among patients with
WAICH. Recent American Heart Associa-
tion guidelines state that careful control of
the anticoagulation level decreases the risk
of ICH.10 However, no practical knowl-
edge exists to address this important clini-
cal problem.
To assess the risks of resumption or per-
manent discontinuation of warfarin
therapy, we conducted a follow-up study
on a cohort of patients with WAICH who
restarted anticoagulation therapy. We com-
pared their risk with that of a group of pa-
tients with prior WAICH who did not re-
sume warfarin therapy.
METHODS
We analyzed consecutive patients admitted to our
hospital with a diagnosis of WAICH from No-
vember 1, 2001, through December 31, 2005.
Our institutional review board approved the de-
sign of the study. We identified the patients ret-
rospectively using a diagnosis-based electronic
search engine and included them in the study
after detailed analysis of medical records and

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Table 1. Clinical Characteristics a
Restarted Nonrestarted
Group Group
Variable (n = 23) (n = 25)
Age, mean (range), y 70.8 (45-86) 75.3 (45-90) b
Sex, No. M/F 13/10 14/11
Reason for anticoagulation
Atrial fibrillation 9 (39) 14 (56)
Valve replacement 10 (44) 2 (8)
Thrombus/DVT 3 (13) 7 (28)
Other c 1 (4) 2 (8)
Hypertension treated with medication 19 (83) 18 (72)
Diabetes mellitus 5 (22) 6 (24)
Coronary artery disease/CHF 5 (22) 10 (40)
Previous stroke 7 (30) 8 (32)
Concomitant neoplasm 1 (4) 3 (12)
Abbreviations: CHF, congestive heart failure; DVT, deep venous
thrombosis.
a Unless otherwise indicated, data are expressed as number (percentage)
of patients.
b Differences between groups were significant (P = .02).
c Including vertebrobasilar atherothrombotic disease and stroke history.
computed tomographic scans. Inclusion criteria were presenta-
tion to our hospital with radiologically documented ICH, an in-
ternational normalized ratio of 1.5 or higher at admission, cur-
rent treatment with warfarin, and discharge from the hospital. The
ICH volumes were based on computed tomographic scans ob-
tained at presentation and calculated using the formula
(ABC)/2 described by Kothari et al.11
Follow-up data were obtained through a review of medical
records and mailed questionnaires. The questionnaire in-
cluded information on current disability, current use of war-
farin or antiplatelet medications, and information about recur-
rent ICH, ischemic stroke, and other hemorrhagic or
thromboembolic complications that occurred after the origi-
nal ICH. A major hemorrhage or thromboembolic event was
defined as an event requiring hospital admission or requiring
a change in medical anticoagulation therapy. All hemorrhages
were categorized as traumatic or nontraumatic. If the hemor-
rhage occurred in the setting of a fall or trauma, it was consid-
ered traumatic. When sufficient information was available, the
ischemic stroke mechanism was determined.
Patients were divided into those restarting (restarted group)
and not restarting (nonrestarted group) warfarin therapy. Pa-
tients were included in the restarted group if they restarted war-
farin therapy within 60 days of the primary ICH. This 2-month
cutoff was intended to compensate for any other medical con-
dition that would delay reinitiation of warfarin therapy and ac-
counted for at least 1 outpatient hospital follow-up from the
time of discharge, which is typically the time when the deci-
sion to reinitiate warfarin therapy is made. Patients who re-
started warfarin therapy after 60 days were included in the non-
restarted group. When patients in the nonrestarted group were
later prescribed warfarin after an episode of recurrent throm-
boembolism, they were categorized in the restarted group for
the remainder of their follow-up.
Follow-up time was calculated in months, from the pre-
senting month of WAICH to the month of questionnaire re-
sponse or the last neurological examination on file. End points
included nontraumatic or traumatic recurrent ICH, abnormal
bleeding requiring hospitalization, ischemic stroke, myocar-
dial infarction, other thrombotic and thromboembolic events
(pulmonary embolism, peripheral arterial embolism, and deep
vein thrombosis), and the cause and time of death. Intracra-
nial hemorrhage was subdivided into subdural or subarach-
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noid hemorrhage. Functional outcome was evaluated using the
modified Rankin Scale score measured at hospital discharge and
latest follow-up by reviewing physical examination results and
questionnaire answers.12,13
We used a 2-sample t test for comparison of age between
the restarted and nonrestarted groups. Modified Rankin Scale
scores at discharge and most recent follow-up were described
and compared between groups using a 2-sample t test. The end
points of death, recurrent nontraumatic ICH, ICH, or throm-
boembolic events were analyzed using the Kaplan-Meier method,
with log-rank tests for comparisons between groups. Cox pro-
portional hazards regression was used to estimate the hazard
ratio and 95% confidence interval.
RESULTS
Of the 88 consecutive patients identified with WAICH,
only 52 (59%) were discharged from the hospital. The
other 36 patients died in the hospital or in hospice care.
Of the 52 discharged patients, 23 (44%) restarted war-
farin therapy. Twenty-nine of the 52 patients (56%) did
not restart warfarin therapy; 4 of these patients could not
be reached to obtain follow-up information and were not
included in the analysis. The clinical and radiological char-
acteristics of our study population are detailed in Table 1
and Table 2. Mean age was higher in the nonrestarted
group (75.3 vs 70.8 years). Most of the patients in the
restarted group (10 patients [44%]) required warfarin for
thromboembolic prevention owing to implantation of a
prosthetic valve, a much higher proportion with this in-
dication than among patients in the nonrestarted group.
Of the 10 patients who reinitiated warfarin therapy be-
cause of mechanical valves, 8 had aortic valve replace-
ments and 2 had both aortic and mitral valve replace-
ments. Aortic valve replacements included 3 St Jude valves,
2 Star-Edwards valves, 1 caged-ball valve, 1 Brunwald-
Cutter valve, and 1 Medtronic allograft valve. Both of the
patients with aortic and mitral valve replacements had
St Jude valves. Patients restarted warfarin therapy after
a median of 10 (range, 7-28) days.
Fourteen of the 25 patients (56%) in the nonre-
started group originally received warfarin for atrial fi-
brillation. One of the 2 patients with a history of valve
surgery who did not restart warfarin therapy had a Car-
pentier-Edwards valve and mitral valve repair. This pa-
tient did not restart warfarin therapy owing to concern
about having another ICH. In the 34 months of follow-
up, the patient reported a myocardial infarction but no
other thromboembolic complications. The other pa-
tient had an aortic valve that had been replaced with a
St Jude valve and did not restart warfarin therapy owing
to comorbid medical concerns, specifically an abdomi-
nal aortic aneurysm, a right coronary artery aneurysm,
and worsening congestive heart failure. The patient died
1 month after discharge from the hospital.
Locations of ICHs were generally similar between
groups. In the restarted group, a slightly higher percent-
age of patients (10 vs 8 patients [43% vs 32%]) had lo-
bar hemorrhage. Conversely, cerebellar hemorrhages (4
vs 2 patients [16% vs 9%]) and intraventricular hemor-
rhages (2 vs 1 patient [8% vs 4%]) were more common
in the nonrestarted group (Table 2).
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 Table 2. Hemorrhage Characteristics

Restarted Group (n = 23) Nonrestarted Group (n = 25)

Mean Volume, Mean Volume,

Location No. (%) mL No. (%) mL
Lobar 10 (43) 20.1 8 (32) 14.9
Deep 8 (35) 6.5 9 (36) 6.2
Cerebellar 2 (9) 14.6 4 (16) 10.6
Brainstem/pons 2 (9) 2.2 1 (4) 1.1
Intraventricular 1 (4) NA 2 (8) NA
Multiple areas 0 NA 1 (4) 14.4

Abbreviation: NA, not applicable.

Mean follow-up among all patients was 43 months.

Median follow-up was 36 (range, 1-100) months. At the Table 3. Follow-up Data in 48 Patients With
Warfarina-Associated ICH
time of last follow-up, mortality was high in both groups:
13 of the 23 patients in the restarted group and 12 of the
Restarted Nonrestarted
25 nonrestarted group had died. Survival outcomes were Group Group
assessed using the log-rank outcome. Although the dif-
Mean follow-up, mo 49.8 36.1
ferences were not significant, there was a trend for those Mean mRS score
who restarted warfarin therapy to survive early after reini- At discharge 3.1 2.6
tiation of drug therapy. At 1 year, there was a 96% sur- At latest follow-up 4.6 3.7
vival (SD, 4%) in the restarted group and a 76% survival Mean time to death, mo 55.6 21.8
(SD, 8.5%) in the nonrestarted group. At 2 years, the sur- End point events, No. of patients
vival changed to 86% (SD, 14%) vs 68% (SD, 32%) in Thromboembolic stroke 0 3
Thromboembolism, nonstroke 0 2
both groups. The average time to death appeared shorter
Nonembolic ischemic stroke 2 2
in the nonrestarted group than in the restarted group (21.8 Nontraumatic ICH 1 0
vs 55.6 months). The modified Rankin Scale scores were Traumatic ICH 2 0
similar, and showed worsening of disability from time GI hemorrhage 2 2
of discharge to current follow-up. Details of follow-up Myocardial infarction 4 6
data are given in Table 3.
There were 5 cases of recurrent major hemorrhage in Abbreviations: GI, gastrointestinal tract; ICH, intracranial hemorrhage;
mRS, modified Rankin Scale.
the restarted group, including 1 recurrent WAICH, 2 trau- aWarfarin is as warfarin sodium.
matic ICHs, and 2 extracranial bleedings. Three of the 5
events were fatal. The patient with the recurrent non-
traumatic WAICH had a fatal deep hematoma contralat- complications. Categorizing these 2 patients in the re-
eral to the side of the original bleeding that occurred 35 started group after reinitiation of warfarin therapy did
months after reinitiating warfarin therapy (Figure 1). not change the results of the survival analysis or out-
Of the traumatic ICHs, one was primarily subarachnoid come between the groups.
and resulted in death, whereas the other was a nonfatal Other complications were noted in both groups. There
small subdural hemorrhage. Of the 2 extracranial hem- were 2 ischemic strokes in the nonrestarted group that were
orrhages, one was a fatal pulmonary hemorrhage and the not attributed to thromboembolism. One was ascribed to
other was a soft tissue abdominal wall hematoma requir- penetrating artery disease and the other to infectious en-
ing hospital admission. In the cases of the fatal recur- docarditis. Two patients who did not restart warfarin therapy
rent nontraumatic WAICH and traumatic subarachnoid had gastrointestinal tract bleeding. One case occurred 1
hemorrhage, the international normalized ratios at pre- month after the WAICH and was fatal; the other required
sentation were 2.5 and 4.1, respectively. hospital admission and was related to aspirin use.
Among the patients who did not restart warfarin Although examination of the Kaplan-Meier curves sug-
therapy, there were 5 cases of thromboembolic events, gests that an adverse event (major hemorrhage or throm-
including 3 thromboembolic strokes (all attributed to atrial boembolic event) occurred sooner in the nonrestarted
fibrillation), 1 pulmonary embolus, and 1 distal arterial group, this difference was not significant (Figure 2).
embolus resulting in leg ischemia. Only 1 case was fatal. Overall, 5 of the 25 patients in the nonrestarted group
All thromboembolic events occurred in patients who origi- had thromboembolic complications compared with only
nally received warfarin for secondary prevention of throm- 1 of the 23 patients who experienced recurrent nontrau-
boembolism. Among the patients with thromboembolic matic WAICH in the restarted group. When all intracra-
strokes, the mean time to the event was 5.7 (range, 3-7) nial hemorrhages were included, 3 of 23 patients expe-
months; 2 of these patients reinitiated warfarin therapy rienced a subdural hematoma, subarachnoid hemorrhage,
at the time of the stroke, and in 1 patient the stroke was or recurrent nontraumatic WAICH. The difference be-
fatal. The 2 patients who restarted warfarin therapy af- tween the restarted and nonrestarted groups for the end
ter an embolic stroke had no subsequent hemorrhagic point of thromboembolic events and WAICH was not sta-

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 A B

Figure 1. Computed tomographic scans show original bleeding (A) and a fatal deep hematoma on the side contralateral to the original bleeding that occurred 35
months after reinitiating warfarin sodium therapy (B).

our knowledge, compares the outcome of patients who

1.0 restarted warfarin therapy with those of patients who did
not restart therapy after a WAICH. Although there were
0.8 no statistically significant differences, the observational
Proportion Event Free

results of our study suggest that recurrent primary ICH

0.6
0.4
0.2 Nonrestarted group
Restarted group
0.0
0 25 50 75
Follow-up, mo
Figure 2. Survival analysis in patients free of major hemorrhage or
thromboembolic events during follow-up.
tistically significant (P = .62), with a hazard ratio of 1.4
(95% confidence interval, 0.4-4.9) for the nonrestarted
vs restarted groups. Furthermore, when all hemor-
rhagic and thromboembolic events were considered as a
combined end point, there was no significant difference
between the groups.
Survival analysis showed that 86.1% of the patients
in the nonrestarted group were free of thromboembolic
complication after 1 year, whereas 73.6% were free of
thromboembolic event after 3 years. When all ICH events
were accounted for, 100% of the patients who restarted
warfarin therapy were free of ICH after 1 year, whereas
92.9% of the patients were free of ICH at 3 years (95%
confidence interval, 80.3%-100.0%).
COMMENT
This study provides the longest clinical follow-up of pa-
tients presenting with WAICH and for the first time, to
after reinstitution of warfarin therapy occurs less fre-
quently than does recurrent thromboembolic events in
patients who do not restart warfarin therapy. However,
reinitiating anticoagulation therapy was also associated
with an increased risk of traumatic ICH and extracra-
nial hemorrhagic complications.
Two previous studies addressed the outcomes of pa-
100 125
tients who reinitiated warfarin therapy after ICH. One
study followed up 13 patients with ICH and prosthetic
heart valves for 2 years and reported no cases of recur-
rent nontraumatic ICH.14 Another study described 25 pa-
tients who restarted warfarin therapy after ICH with no
episodes of recurrent ICH after anticoagulation was re-
started, but the length of follow-up after reinitiating an-
ticoagulation therapy was not provided.15 A recent analy-
sis of estimated ICH recurrence, not restricted to WAICH,
concluded that the risk would be 2.3% per patient per
year.16 In our series, recurrent primary WAICH was un-
common (1 of 23 patients) after reinitiation of antico-
agulation therapy, whereas ICH occurred in 3 of 23 pa-
tients.
The percentage of thromboembolic complications in
patients who did not restart warfarin therapy was sub-
stantial, despite a lower incidence of patients with me-
chanical prosthetic valves. All patients with thrombo-
embolic events after WAICH had originally started
warfarin therapy after a thromboembolic event. This sug-
gests that patients requiring warfarin for secondary (as
opposed to primary) prevention of thromboembolic events
may be more likely to benefit from reinitiation of war-
farin therapy after WAICH. Recurrent thromboembolic
strokes occurred mostly within 6 months of the WAICH,

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suggesting that early reinitiation of warfarin therapy may
be advantageous. In our population, most patients re-
started warfarin therapy within 2 weeks of the WAICH.
This practice was guided by previous data indicating that
there is a low probability of thromboembolic events in
patients with mechanical valves within the first 2 weeks
after an ICH.17
Our study results confirm the poor outcomes of pa-
tients with WAICH and the frequent adverse effects at-
tributable to warfarin. A recent study of patients with atrial
fibrillation who were hospitalized for ICH and extracra-
nial hemorrhage attributed to warfarin use had a mean
follow-up of 2.4 years.18 It concluded that mortality and
long-term disability were high in patients with ICH,
whereas those with extracranial hemorrhage survived with
minor or no disability. In our patients, mortality during
follow-up was high (48%), and functional scores wors-
ened over time. The average time to death was much
shorter in the nonrestarted group. One possible expla-
nation is that these patients were older than those in the
restarted group. However, there may have been other
medical problems that could have contributed to this dif-
ference and likely influenced the decision to discon-
tinue warfarin therapy permanently after the ICH.
Hemorrhage risk is well described in patients taking
warfarin. Aside from ICH, extracranial sites such as the
gastrointestinal tract, genitourinary tract, and soft tis-
sue are common sites for hemorrhage.19-21 Patients who
have had previous hemorrhagic events while receiving
warfarin are at increased bleeding risk. Other risk fac-
tors include liver and renal disease, hypertension, can-
cer, and stroke.19,22-25 Among our patients who restarted
warfarin therapy, recurrent hemorrhages were fatal in 3
of 5 cases, thus confirming the severity of recurrent hem-
orrhagic complications in patients receiving anticoagu-
lation therapy.
The data often cited to guide clinicians on the risks
and benefits of restarting anticoagulation therapy after
WAICH are derived from a computer model based on hy-
pothetical strategies and a decision analysis that made
predictions based on certain assumptions of risk.26 Un-
derlying assumptions used in this model include that the
risk of recurrent ICH is constant over a patients life-
time, and that any ICH should result in permanent dis-
continuation of anticoagulation therapy. Although this
model is helpful in conceptualizing this difficult clinical
problem, its conclusions need to be interpreted with cau-
tion because it was built using assumptions not con-
firmed by actual clinical data. For instance, the model
recommends that, in patients with deep hemorrhage, an-
ticoagulation therapy should be permanently withheld
owing to concern about recurrent hemorrhage unless there
is a high risk of ischemic stroke.
The main limitation of this retrospective study is that
we could not control for the clinical differences and time
of follow-up between the 2 groups. For instance, the re-
started group was younger and included a higher pro-
portion of patients with a mechanical valve prosthesis.
Although patients with prosthetic valves are at greater
risk of thromboembolic events, our data indicated that
they had fewer thromboembolic events than patients who
did not restart warfarin therapy. This observation rein-
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forces the benefit of anticoagulation therapy in patients
with mechanical valves. Unfortunately, a randomized con-
trolled study addressing the clinical decision of restart-
ing warfarin therapy after a WAICH is unlikely to be con-
ducted. The decision for randomization would probably
be deemed unsafe in certain patients; for example, a pa-
tient with a prosthetic valve is more likely to have war-
farin therapy restarted than is a patient with atrial fibril-
lation and severe neurological deficits after a stroke.
Therefore, we have to rely on observational data to evalu-
ate this clinical problem. In addition, 4 patients were lost
to follow-up. All of these patients were in the nonre-
started group, and this discrepancy could have gener-
ated a bias.
This is, to our knowledge, the first long-term clinical
study comparing the outcomes in patients with or with-
out reinitiation of warfarin therapy after a WAICH. Our
clinical data indicate that recurrent WAICH is uncom-
mon when anticoagulation therapy is resumed, whereas
the risk of thromboembolic events may be compar-
atively greater in patients who do not reinitiate warfarin
therapy. However, the clinician deciding whether to re-
start anticoagulation therapy after an episode of WAICH
should weigh other factors, including the patients risk
of falls, general medical condition, and other risk fac-
tors for systemic hemorrhage. Patients without these risks
may benefit from reinstitution of warfarin therapy. Fail-
ure to do so might unnecessarily subject them to throm-
boembolic complications.
Accepted for Publication: May 7, 2008.
Correspondence: Alejandro A. Rabinstein, MD, Depart-
ment of Neurology, Mayo Clinic, W8B, 200 First St SW,
Rochester, MN 55905 (rabinstein.alejandro@mayo
.edu).
Author Contributions: Study concept and design: Claas-
sen, Kazemi, Wijdicks, and Rabinstein. Acquisition of data:
Claassen, Kazemi, and Zubkov. Analysis and interpreta-
tion of data: Claassen, Kazemi, Wijdicks, and Rabin-
stein. Drafting of the manuscript: Claassen, Kazemi, and
Wijdicks. Critical revision of the manuscript for impor-
tant intellectual content: Kazemi, Zubkov, and Rabin-
stein. Statistical analysis: Claassen and Kazemi. Admin-
istrative, technical, and material support: Zubkov. Study
supervision: Wijdicks and Rabinstein.
Financial Disclosure: None reported.
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New Initiatives: Clinical Trials and Videos

We have embarked on 2 new initiatives: Clinical Trials

and video presentations. We welcome manuscripts that
describe double-blind, randomized, placebo-controlled
clinical trials as our primary area of interest. Open-label
studies will also receive our special attention. We plan
on expediting the review process and time to publica-
tion and to include them online ahead of print as these
studies are time sensitive and of direct benefit to our pa-
tients. We hope you will take advantage of this new ini-
tiative. Please refer to the Instructions for Authors when
submitting a Clinical Trials paper, including the require-
ment to register the trial with an accepted clinical trials
site.
We plan to utilize videos as part of published papers
that highlight and provide convincing information about
the observational and visual features of a patients neu-
rologic findings. Please refer to Instructions for Au-
thors for instructions on submitting video presentations.

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