LMWH Reduces Early Neurologic Deterioration in Acute Stroke Patients with Large Artery Occlusive Disease

ORIGINAL CONTRIBUTION
Low-Molecular-Weight Heparin and Early Neurologic
Deterioration in Acute Stroke Caused
by Large Artery Occlusive Disease
Qiaoshu Wang, MD; Christopher Chen, FRCP; Xiang Yan Chen, MD; Jing Hao Han, MD; Yannie Soo, MD;
Thomas W. Leung, MD; Vincent Mok, MD; Ka Sing Lawrence Wong, FRCP
Background: Patients with acute ischemic stroke and
large artery occlusive disease (LAOD) have an in-
creased risk for early neurologic deterioration (END) due
to progressive stroke, early recurrent ischemic stroke
(ERIS), or symptomatic intracranial cerebral hemor-
rhage (SICH). Low-molecular-weight heparin (LMWH)
has been widely advocated to prevent venous thrombo-
embolism, but its risks and benefits in early ischemic
stroke are inadequately defined.
Objective: To determine the efficacy and safety of
LMWH in treating END in patients with acute ischemic
stroke and LAOD.
Design: Post hoc analysis of randomized, controlled trial.
Setting: Academic research.
Patients: Among 603 patients recruited, 353 patients
(180 treated with LMWH, 173 with aspirin) had acute
ischemic stroke and LAOD.
Interventions: Patients were randomly assigned to re-
ceive either subcutaneous LMWH or oral aspirin within
48 hours after stroke onset for 10 days, then all received
aspirin once daily for 6 months.
Main Outcome Measures: We assessed whether
LMWH was superior to aspirin for the prevention of END
within the first 10 days after index stroke. Early neuro-
logic deterioration was defined as a composite end point
of progressive stroke, ERIS, and SICH.
Results: Among 353 patients included in the study, END
within the first 10 days occurred in 6.7% of LMWH-
allocated patients (12 of 180 patients) compared with
13.9% of aspirin-allocated patients (24 of 173). Low-
molecular-weightheparinwassignificantlyassociatedwith
the reduction of END (absolute risk reduction, 7.2%; odds
ratio [OR], 0.44; 95% CI, 0.21-0.92). When individual
components of END were examined, LMWH was sig-
nificantly associated with a lower frequency of stroke pro-
gression within the first 10 days compared with aspirin
(5.0% [9 of 180] vs 12.7% [22 of 173]; OR, 0.36; 95%
CI, 0.16-0.81). Meanwhile, among those taking LMWH
vs aspirin, the frequency rates of ERIS were 1.1% (2 of
180) vs 0 (0); 0.6% (1 of 180) vs 1.2% (2 of 173) for SICH;
and 2.2% (4 of 180) vs 2.9% (5 of 173) for symptomatic
and asymptomatic cerebral hemorrhage, respectively; they
showed nonsignificant trends. Early neurologic deterio-
ration was significantly associated with 6-month disabil-
ity with both LMWH (OR, 12.75; 95% CI, 3.27-49.79 on
Barthel Index and OR, 18.15; 95% CI, 2.09-157.93 on
modified Rankin Scale) and aspirin (OR, 6.09; 95% CI,
2.44-15.20 on Barthel Index and OR, 7.50; 95% CI, 2.08-
27.04 on modified Rankin Scale) groups.
Conclusions: For patients with acute ischemic stroke
and LAOD, treatment with LMWH within 48 hours of
stroke may reduce END during the first 10 days, mainly
by preventing stroke progression. The similar rate of ce-
rebral hemorrhage between LMWH and aspirin demon-
strated that LMWH may be safely used in acute ische-
mic stroke.
Trial Registration: strokecenter.org/trials Identifier:
FISS-tris
Arch Neurol. 2012;69(11):1454-1460. Published online
August 13, 2012. doi:10.1001/archneurol.2012.1633
P
ATIENTS WITH LARGE ARTERY
occlusive disease (LAOD) are
at high risk for early neuro-
logicdeterioration(END)and
have the highest odds of early
recurrent ischemic stroke (ERIS).1,2
Large
artery occlusive disease due to intracranial
atherosclerosis is an important cause of
stroke,3-5
and the risk for recurrent stroke
may be greater than for extracranial ca-
rotidatherosclerosis,especiallyinAsianand
Hispanic populations.6
For these patients,
treatment with aspirin has limited benefits
and intensive clinical research is required
to develop more effective interventions.7-9
CME available online at
www.jamaarchivescme.com
Author Affil
Department
Shanghai Fir
Hospital, Sha
University Sc
Shanghai (D
Departments
Therapeutics
University o
Kong Specia
Region (Drs
Soo, Leung,
China; and D
Pharmacolog
University o
Singapore (D
Author Affiliations are listed at
the end of this article.
ARCH NEUROL/VOL 69 (NO. 11), NOV 2012 WWW.ARCHNEUROL.COM
1454
©2012 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of St. Andrews Library User on 05/20/2015

Anticoagulation is a controversial treatment option for
early secondary prevention, as the results of clinical trials
remain inconclusive. For patients with symptomatic in-
tracranial stenosis, while retrospective data have sug-
gested that warfarin was superior to aspirin for the pre-
vention of recurrent ischemic stroke,10
the prospective
Warfarin-Aspirin Symptomatic Intracranial Disease study
was stopped early owing to safety concerns about exces-
sive adverse events in the warfarin group together with
no signal for effectiveness.11
Likewise, beneficial effects
were not observed for low-molecular-weight heparin
(LMWH) within 2 weeks of treatment in the Heparin in
Acute Embolic Stroke Trial study, a randomized trial for
early recurrence in patients with acute ischemic stroke
and atrial fibrillation (AF).12
However, in the Interna-
tional Stroke Trial study, unfractionated heparin re-
duced ischemic stroke recurrence during the period of
treatment.8
Furthermore, hemorrhagic transformation was
also observed in these studies and was associated with
anticoagulation using unfractionated heparin and
LMWH,8,13,14
and it may be of importance as both ERIS
and hemorrhagic transformation cause END.
We have previously reported15
that hemorrhagic trans-
formation in patients with LAOD was similar between
LMWH-treated and aspirin-treated patients. However,
clinical differences between LMWH and unfractionated
heparin are likely the results of their distinct pharmaco-
kinetic profiles.16
To our knowledge, the efficacy of
LMWH in preventing END has not been examined, hence
we report a post hoc analysis of a randomized aspirin-
controlled trial exploring the efficacy and safety of LMWH
for END in patients with acute ischemic stroke and LAOD.
METHODS
DESIGN
The design of the Fraxiparin in Stroke Study for the treatment
of ischemic stroke (FISS-tris) has been published.15
In short,
the study was a prospective multicenter, randomized clinical
trial conducted at multiple trial sites in Hong Kong and Sin-
gapore with ethics committee approval, and it was designed to
compare LMWH with aspirin for the early treatment of pa-
tients with LAOD and acute ischemic stroke. Randomization
into the trial was done through the central randomization of-
fice at the Clinical Trials and Epidemiology Research Unit in
Singapore by means of sealed envelopes or allocation via the
Internet. Block randomization was used (block sizes of 4 and
6), stratified by regions (Hong Kong, Kowloon, New Territo-
ries, and Singapore), time from onset of stroke (0-24 hours or
24-48 hours), National Institute of Health Stroke Scale (NIHSS)
score (0-8 or Ն9), and whether neurovascular investigations
were done before randomization (vascular lesion present or sta-
tus unknown), with a one-to-one treatment allocation. The treat-
ment assignment was generated by computer. Written in-
formed consent was obtained from all participants or their legally
acceptable representatives. This study is registered at http://
www.strokecenter.org/trials (identifier FISS-tris).
PARTICIPANTS
The target population was defined as patients diagnosed as hav-
ing acute ischemic stroke and with LAOD who could be treated
with either nadroparin calcium, 3800 antifactor Xa IU/0.4 mL,
subcutaneously twice daily (LMWH group) or aspirin, 160 mg,
once daily (aspirin group) within 48 hours after stroke onset
for 10 days, then all received aspirin, 80-300 mg, once daily
for 6 months. All patients underwent a computed tomo-
graphic head scan before randomization and a repeat com-
puted tomographic scan at day 10 (or a computed tomographic/
magnetic resonance image earlier in case of rapid and severe
neurologic deterioration). Vascular imaging was performed to
identify moderate or greater stenosis in the internal carotid, ver-
tebrobasilar, middle cerebral, anterior cerebral, and posterior
cerebral arteries by carotid duplex scan, transcranial Doppler
imaging, or magnetic resonance angiography, according to pre-
viously published criteria.17,18
Vascular evaluation was done be-
fore or within 3 days after randomization, and only patients
with symptomatic LAOD were included in the analysis. Other
exclusion criteria are as previously described.15
FOLLOW-UP, EVENTS,
AND OUTCOMES
The patients were randomized following a central randomiza-
tion code to 2 treatment groups, subcutaneous LMWH or oral
aspirin, and baseline data were collected including demograph-
ics, medical history, prestroke modified Rankin Scale (mRS) and
NIHSS scores. The primary outcome event for this analysis was
END defined as an increase of 4 points or more on the NIHSS
explainable by the stroke event at 10 days from baseline or death
owing to a stroke event during the same period.13,19,20
Early neu-
rologic deterioration was also a composite end point including
progressive stroke, ERIS, and symptomatic intracranial cere-
bral hemorrhage (SICH).19,20
Progressive stroke was defined as
strokeeventsofENDwithoutevidenceofERISorSICH.19,20
Symp-
tomatic intracranial cerebral hemorrhage was classified to be the
cause of END when a parenchymal hematoma was identified on
post-treatment computed tomography.21
Early recurrent ische-
mic stroke was defined as a sudden and persistent (Ͼ24 hours)
deficit occurring after index stroke onset, with both clinical and
imaging findings of ischemic stroke diagnosed in an indepen-
dent artery separated from index stroke territory.20
At day 10, or earlier if discharged from the hospital, trained
personnel performed the NIHSS and Barthel Index. Favorable
outcomes were defined as a Barthel Index score of at least 85
points as used in the FISS bis study.22
The END, progressive
stroke, ERIS, and SICH were assessed by physicians who were
aware of the treatment assignments. At 6 months after ran-
domization, Barthel Index and mRS scores were assessed by a
clinician or a nurse without knowledge of the treatment allo-
cation. Disability was identified as a Barthel Index score of 80
or less or mRS score of 2 or greater in survivors.
STATISTICAL ANALYSIS
All analyses were performed according to the intent-to-treat prin-
ciple. Frequencies of events and outcomes were compared with
the ␹2
test. If the number in any group was less than 5, the Fisher
exact test was preferred. The effect of treatment was expressed
as odds ratios (ORs) with 95% confidence intervals; OR values
of greater than 0 and less than 1 indicated an advantage of
LMWH over aspirin for END. Comparisons of baseline char-
acteristics also involved t test and ␹2
with 2-sided P values to
show significance. For a better identification of patients at risk
for END or bad outcome, adjustment for the confounding ef-
fect of variables was achieved by logistic regression analysis.
The primary model was based on the 5 hypothesized contribu-
tors to the risk for END: baseline NIHSS score, age, hyperten-
sion, diabetes mellitus, and hyperlipidemia. Additional vari-
ables were considered for inclusion in the multivariable model
1455

if they could be associated with END in univariate analysis at
the PϽ.05 level. Odds ratios and their 95% confidence inter-
vals were used to evaluate the association of END with the risk
for death and disability within 6 months of stroke. Descriptive
statistics were reported as median values with 25th to 75th per-
centiles. The analysis was carried out using SPSS version 15.0
(SPSS Inc).
RESULTS
In the FISS-tris study, 603 patients with acute ischemic
stroke were enrolled in 11 hospitals in Hong Kong and
Singapore, of whom 353 patients were confirmed as
having LAOD. The location of LAOD was solely intra-
cranial in 300 patients (85%), solely extracranial in 11
patients (3%), and both intracranial and extracranial in
42 (12%). Altogether, 10 patients ended treatment be-
fore 10 days owing to death (n=1), cerebral hemor-
rhage (n=3), neurologic deterioration (n=1), extrace-
rebral hemorrhage (n=3), esophageal ulcer (n=1), and
elevated liver enzymes (n=1). Overall compliance with
the study medication was 96.7% (174 of 180 patients)
in the LMWH group and 97.7% (169 of 173) in the as-
pirin group. In our study, we included only those
whose cause of END was stroke event. We excluded 5
patients who also had an increase of 4 or more points on
the NIHSS within the first 10 days, but whose cause of
deterioration was not stroke (3 patients in the aspirin
group with pneumonia, continuing hematuria, and di-
arrhea; and 2 in the LMWH group with severe hema-
toma on the scalp and pneumonia). Among the 5 pa-
tients, 1 died from chest infection and the others had
transient neurologic worsening that occurred within
the first 10 days and the deficit reversed after the con-
dition was controlled.
PATIENT CHARACTERISTICS
ThebaselinecharacteristicsofpatientsbetweentheLMWH
and aspirin groups were well balanced, except for higher
levels of triglycerides in the LMWH group (P=.01).
Table 1 presents the baseline characteristics of patients
with END (more elderly patients in the aspirin group,
higher NIHSS scores in the LMWH group) and without
END (more patients with hypertension in the aspirin
group).
EVENTS
There was a significance difference (absolute risk reduc-
tion, 7.2%; OR, 0.44; 95% CI, 0.21-0.92) in the fre-
quency of deterioration during the first 10 days of acute
ischemic stroke with LAOD (12 of 180 [6.7%] in the
LMWH group vs 24 of 173 [13.9%] in the aspirin group,
which indicated as an advantage of LMWH over aspirin;
Table 2).
Treatment with LMWH was significantly associated
with a lower frequency of stroke progression during the
first 10 days (9 of 180 [5.0%] vs 22 of 173 [12.7%]; ab-
solute risk reduction, 7.7%; OR, 0.36; 95% CI, 0.16-
0.81) (Table 2). Of the patients with progressive stroke,
9 had abrupt courses (2 taking LMWH and 7 taking as-
pirin) and 22 had progressive courses (7 taking LMWH
and 15 taking aspirin).
There was no significant difference in the frequency
of ERIS during the first 10 days: 2 patients (1.1%) in the
LMWH group and none in the aspirin group (Table 2).
One of the 2 cases of ERIS had new-onset AF on day 2
without documentation of AF on hospital admission or
in the medical history.
Table 1. Baseline Characteristics of Patients With and Without END
LMWH
(n = 180), No. (%)
P Value
Aspirin
(n = 173), No. (%)
P Value
Without END
(n = 168)
With END
(n = 12)
Without END
(n = 149)
With END
(n = 24)
Age, median (25th-75th percentile), y 70 (62-75) 69 (64-78) .45 67 (59-74) 73 (68-76) .03
Male 99 (59) 7 (58) .97 86 (58) 14 (58) Ͼ.99
Risk factors
History of stroke/TIA 34 (20) 5 (42) .08 27 (18) 6 (25) .43
Ischemic heart disease 20 (12) 0 (0) 14 (9) 1 (4) .70
Hypertension 131 (78) 10 (83) Ͼ.99 122 (82) 14 (58) .01
Diabetes mellitus 67 (40) 6 (50) .49 71 (48) 16 (67) .08
Hyperlipidemia 77 (46) 9 (75) .07 67 (45) 15 (63) .11
Smoking history 75 (45) 7 (58) .36 61 (41) 15 (63) .05
Alcoholism 25 (15) 1 (8) Ͼ.99 26 (17) 4 (17) Ͼ.99
Fasting glucose levels, median, mmol/L,
25th-75th percentile
5.70 (4.80-7.68) 6.45 (5.30-8.10) .65 5.80 (4.90-7.85) 6.75 (5.10-7.60) .58
Fever 5 (3) 1 (8) .34 7 (5) 3 (13) .15
NIHSS score, median (25th-75th percentile) 6 (4-9) 9 (5-13) .04 6 (4-9) 8 (5-12) .10
0-8 122 (73) 6 (50) .10 107 (72) 15 (63) .35
Ն9 46 (27) 6 (50) .10 42 (28) 9 (38) .35
Previous and ongoing medication
Antiplatelet agents 53 (32) 7 (58) .06 51 (34) 7 (29) .63
Abbreviations: END, early neurologic deterioration; LMWH, low-molecular-weight heparin; NIHSS, National Institutes of Health Stroke Scale; TIA, transient
ischemic attack.
1456

AlsononsignificantlydifferentwasthefrequencyofSICH
during the first 10 days: 1 patient (0.6%) taking LMWH
vs 2 (1.2%) taking aspirin (OR, 0.48; 95% CI, 0.04-5.32),
as was the frequency of symptomatic and asymptomatic ce-
rebral hemorrhage identified by brain imaging: 4 (2.2%)
taking LMWH vs 5 (2.9%) taking aspirin (OR, 0.76;
95% CI, 0.20-2.89). However, extracerebral hemorrhages
occurring in the LMWH-allocated patients were more
frequent (OR, 2.22; 95% CI, 0.67-7.35) (Table 2).
In the LMWH group, during the first 10 days, 1 pa-
tient was diagnosed as having increased intracranial pres-
sure owing to brain edema caused by a middle cerebral
artery occlusion and underwent craniectomy, and an-
other patient died of pneumonia.
OUTCOMES
At day 10, there was no significant association between
favorable outcomes and LMWH, as assessed by a Bar-
thel Index score of at least 85 points (79 of 180 [43.9%]
taking LMWH vs 67 of 173 [38.7%] taking aspirin; OR,
1.24; 95% CI, 0.81-1.89; P = .33, unadjusted, and P = .71,
adjusted).
Table 3 shows the frequency of 6-month disability
and 6-month death in the FISS-tris cohort according to
the presence and type of END and aspirin/LMWH allo-
cation. The Figure illustrates the ORs for 6-month dis-
ability and 6-month death rates according to the pres-
ence of END and LMWH/aspirin allocation. Odds ratios
were adjusted for baseline NIHSS score, age, hyperten-
sion, diabetes mellitus, and hyperlipidemia. After adjust-
ment, END significantly influenced the risk for 6-month
0.01 0.1 1 10 100
Favors Patients
With END
Odds Ratio
M-H Fixed-Effects Model; 95% CI
Favors Patients
Without END
Disability: LMWH (BI)
Disability: Aspirin (BI)
Disability: LMWH (mRS)
Disability: Aspirin (mRS)
Death: LMWH
Death: Aspirin
Figure. Odds ratios and 95% confidence intervals (CIs) for 6-month
disability and 6-month death rates among patients with and without early
neurologic deterioration (END) in the low-molecular-weight heparin (LMWH)
and aspirin groups. Odds ratios were adjusted for age, hypertension,
diabetes mellitus, hyperlipidemia, and National Institutes of Health Stroke
Scale score. BI indicates Barthel Index; M-H, Mantel-Haenszel; mRS,
modified Rankin Scale.
Table 2. Events at 10 Daysa
No. (%)
OR (95% CI) P Value P Valueb
LMWH
(n = 180)
Aspirin
(n = 173)
Early neurologic deterioration 12 (6.7) 24 (13.9) 0.44 (0.21-0.92) .03 .02
Progressive stroke 9 (5.0) 22 (12.7) 0.36 (0.16-0.81) .01 .008
Early recurrent ischemic stroke 2 (1.1) 0
Symptomatic intracranial hemorrhage 1 (0.6) 2 (1.2) 0.48 (0.04-5.32) .62 .73
Symptomatic and asymptomatic intracranial hemorrhage 4 (2.2) 5 (2.9) 0.76 (0.20-2.89) .75 .87
Extracerebral hemorrhage 9 (5.0) 4 (2.3) 2.22 (0.67-7.35) .25 .18
Death 1 (0.6)
Transient ischemic attack 1 (0.6) 0
Deep venous thrombosis 0 1 (0.6)
Atrial fibrillation/congestive heart failure 1 (0.6) 0
Pneumonia 4 (2.2) 2 (1.1) 1.94 (0.35-10.75) .69 .90
Abbreviations: LWMH, low-molecular-weight heparin; OR, odds ratio.
aAll analyses conducted by ␹2
test or Fisher exact test of association between categorical variables; odds ratio Ͻ1 indicated the advantage of LMWH over aspirin.
bAdjusted for age, hypertension, diabetes mellitus, hyperlipidemia, National Institutes of Health Stroke Scale score, and triglycerides.
Table 3. Outcome According to Subtypes of END
No. (%)
None END Recurrence Progressive Stroke SICH
LMWH
(n = 168)
Aspirin
(n = 149)
LMWH
(n = 12)
Aspirin
(n = 24)
LMWH
(n = 2)
Aspirin
(n = 0)
LMWH
(n = 9)
Aspirin
(n = 22)
LMWH
(n = 1)
Aspirin
(n = 2)
6-mo disability, BI 31 (18) 30 (20) 9 (75)a 15 (63)a 1 (50) 0 (0) 8 (89) 13 (59) 0 (0) 2 (100)
6-mo disability, mRS,
0-2
62 (37) 68 (46) 11 (92)a 21 (88)a 2 (100) 0 (0) 9 (100) 19 (86) 0 (0) 2 (100)
6-mo death 8 (5) 5 (3) 1 (8) 3 (12) 0 (0) 0 (0) 0 (0) 3 (14) 1 (100) 0 (0)
Abbreviations: BI, Barthel Index; END, early neurologic deterioration; LMWH, low-molecular-weight heparin; mRS, modified Rankin Scale; SICH, symptomatic
intracranial cerebral hemorrhage.
aP Ͻ .01.
1457

disability and the relationship was similar in the LMWH
(OR, 12.75; 95% CI, 3.27-49.79 on the Barthel Index and
OR, 18.15; 95% CI, 2.09-157.93 on mRS) and aspirin (OR,
6.09; 95% CI, 2.44-15.20 on the Barthel Index and OR,
7.50; 95% CI, 2.08-27.04 on mRS) groups. Patients with
END had a nonsignificantly higher risk for death (LMWH:
OR, 1.82; 95% CI, 0.21-15.87; aspirin: OR, 4.11; 95% CI,
0.92-18.49). Early neurologic deterioration and progres-
sive stroke led to higher 6-month disability (Barthel In-
dex and mRS scores, 0-2) in the LMWH group vs the as-
pirin group, but no significant difference was found
(Table 3).
COMMENT
The FISS-tris trial was designed to evaluate the efficacy
of LMWH in the treatment of acute ischemic stroke with
LAOD. Although the study showed there was no signifi-
cant benefit of LMWH over aspirin in patients with LAOD
at 6 months,15
early effectiveness was not examined. To
date, there is no international consensus on END, and
the NIHSS has been widely used in published studies with
a high predictive value of worse outcome. A reasonable
definition might be to consider END as an increase of 4
or more points in the NIHSS, which has been proven to
be valid for cortical and subcortical brain infarction.19-21
As LMWH may play a preventive role on the recurrence
and propagation of thrombus, which presents clinically
as stroke deterioration or progression, our analysis was
performed and the findings suggested that LMWH was
superior to aspirin in patients with acute ischemic stroke
and LAOD for the prevention of END and in particular
stroke progression during the first 10 days. The ob-
served incidence of END in our trial was 10.2% (36 of
353 patients), which was lower than in previous stud-
ies.19,23,24
The reasons for the difference may be attrib-
uted to different definitions of neurologic deterioration
or stroke recurrence, as well as different subtypes of is-
chemic stroke in patients. In the Tinzaparin in Acute Isch-
aemic Stroke study, the frequency of END was similar
at day 10, but there was no difference between LMWH-
treated and aspirin-treated groups.14
In the Trial of ORG
10172 in Acute Stroke Treatment study, by 1 week, the
incidence of END was 10%, with no difference between
the LMWH and placebo groups.13
However, in the Tin-
zaparin in Acute Ischaemic Stroke and Trial of ORG 10172
in Acute Stroke Treatment studies, the rates of stroke sub-
types were 485 of 1486 patients (33%) and 230 of 1268
(18%) with large-vessel strokes, 534 of 1486 (36%) and
306 of 1268 (24%) with small-vessel strokes, and 368 of
1486 (25%) and 266 of 1268 (21%) with cardioembolic
strokes, respectively. Neither of these studies per-
formed subgroup analysis of END according to large-
vessel, small-vessel, or cardioembolic stroke sub-
types.13,14
Hence, to our knowledge, FISS-tris is the only
acute stroke anticoagulation study that has targeted en-
rollment of patients with LAOD, most of whom had in-
tracranial atherosclerosis.
The mechanisms of END may include ERIS, progres-
sive stroke, and SICH.19,20
The definition of ERIS dif-
fered between studies, hence ERIS may be caused by dif-
ferent pathophysiological processes.1,12,19,20,24
We defined
ERIS as not occurring in the original artery of the index
stroke because ERIS found in a new territory may be as-
sociated with other nonatherosclerosis mechanisms, es-
pecially AF.20
Among patients with ERIS in our study,
case 1 was owing to newly diagnosed AF causing bilat-
eral cerebral embolism, while multiple-territory infarct
also occurred in case 2, which may be attributed to em-
bolism from other sources such as aortic arch atheroma.
Electrocardiogram on hospital admission alone is insen-
sitive for AF screening as a result of low sensitivity and
specificity. Moreover, echocardiography was not man-
datory in our study, hence there may be undocumented
sources of cardiac embolism.
In our study, the frequency of stroke progression was
8.8% (31 of 353 patients), which was lower than in pre-
vious studies,19
and LMWH was significantly associated
with a reduction of progressive ischemic stroke. The
causes of progressive stroke were diverse and included
reocclusion, distal embolism, poor collateral circula-
tion of the original artery, brain edema, and excitatory
amino acids. Common stroke mechanisms in patients with
intracranial artery stenosis were the occlusion of a single
penetrating artery or an artery-to-artery embolism.25
In
the Clopidogrel Plus Aspirin Versus Aspirin Alone for
Reducing Embolization in Patients with Acute Sympto-
matic Cerebral or Carotid Artery Stenosis study, micro-
embolic signals were detected in 62.2% of patients with
acute ischemic events and symptomatic intracranial ste-
nosis at baseline,26
suggesting that artery-to-artery em-
bolism may be the leading cause of progressive stroke ow-
ing to the original artery. Both anticoagulants and
antiplatelet agents can suppress microembolic signals and
prevent embolism.26,27
In a FISS-tris substudy, 47 pa-
tients were investigated for microembolic signals detec-
tion and no difference was identified between LMWH and
aspirin.28
Nevertheless, LMWH may be also efficacious
in preventing the propagation of red emboli associated
with blood flow reduction due to LAOD.29
In our study,
there were several methodologic limitations for the as-
sessment of progressive stroke: the collateral blood flow
was not evaluated to explore the hemodynamic factors
and just 1 patient was identified with obviously in-
creased intracranial pressure owing to edema, while more
moderate degrees of brain edema may also cause pro-
gressive stroke.
Consistent with our results, in the International Stroke
Trial study, patients allocated to heparin had signifi-
cantlyfewerrecurrentischemicstrokeswithin14daysthan
patients allocated to aspirin.8
It is difficult to establish
whether there is a difference in the prevention of early
stroke recurrence between heparin and LMWH. How-
ever, the Heparin in Acute Embolic Stroke Trial study re-
ported LMWH did not reduce the risk for early recurrent
stroke in patients with acute ischemic stroke and AF who
weretreatedwithLMWHcomparedwiththosetreatedwith
aspirin.12
The reasons for the difference may be ascribed
todistinctpathophysiologicalmechanismsofstrokegroups
and LMWH may not be efficacious in cardioembolic stroke
as opposed to other stroke subtypes.
In line with other studies, the incidence of sympto-
matic hemorrhage in our study was 0.8% (3 of 353 pa-
1458

tients) and did not differ between LMWH and aspirin,12-14
indicating a low risk for cerebral bleeding complications.
In the FISS-tris study, LMWH was not superior to as-
pirin using the dichotomized Barthel Index outcome mea-
sure after 10 days and 6 months. The difference may be
attributed to the relatively low sensitivity of the Barthel
Index as a measure for mild stroke, with 41% and 71%
of patients achieving a score greater than 85 at 10 days
and 6 months, respectively.15
In our study, patients exhibiting END had a higher
risk for 6-month disability compared with patients with-
out END. Hence, END detected within the first 10 days
of ischemic stroke may be regarded as a marker of bad
outcome. Early neurologic deterioration was also re-
vealed to be an independent predictor of functional out-
come in another study.30
However, as no effective therapy
capable of preventing END or reversing its impact on out-
come has been developed, our study suggested that
LMWH may be a rational choice for patients with LAOD.
In the FISS-tris study, LMWH increased good outcome
at 6 months, as defined by a mRS (0-1) dichotomy.15
Our
current analysis provides further evidence that the ben-
efit may partly be attributed to the effect of LMWH on
the prevention of END. However, other factors may also
have impacted early neurologic worsening and out-
comes such as fever, hyperglycemia, and swallowing dys-
function in acute stroke stage, hence the implementa-
tion of multidisciplinary-supported evidence-based
protocols may be a preferred strategy.
Because FISS-tris was not a blinded study, the find-
ings may be affected by bias, which is an important limi-
tation of the study. Other potential limitations of our study
are related to statistical power and generalizability owing
to the relatively low number of patients with END and the
homogenous study population of Asian ethnicity.
Despite these limitations, the results of our study
suggest that LMWH treatment may have a positive in-
fluence on patients with END and progressive stroke
due to acute ischemic stroke caused by LAOD. Our
study should create interest in further large double-
blind clinical trials with advanced diagnostic aids to ac-
cess the arterial stenosis site and grade on the early an-
ticoagulant therapy in patients with ischemic stroke
because of large-artery atherosclerosis, especially intra-
cranial disease.
Accepted for Publication: April 27, 2012.
Published Online: August 13, 2012. doi:10.1001
/archneurol.2012.1633
Author Affiliations: Department of Neurology, Shang-
hai First People’s Hospital, Shanghai Jiaotong Univer-
sity School of Medicine, Shanghai (Dr Wang), Depart-
ments of Medicine and Therapeutics, Chinese University
of Hong Kong, Hong Kong Special Administrative Re-
gion (Drs X. Y. Chen, Han, Soo, Leung, Mok, and Wong),
China; and Department of Pharmacology, National Uni-
versity of Singapore, Singapore (Dr C. Chen).
Correspondence: Ka Sing Lawrence Wong, Depart-
ments of Medicine and Therapeutics, Chinese Univer-
sity of Hong Kong, Prince of Wales Hospital, Shatin, Hong
Kong Special Administrative Region, China (ks-wong
@cuhk.edu.hk).
Author Contributions: All authors had full access to the
study data and shared responsibility for the final deci-
sion to submit for publication. Study concept and design:
Wang, C. Chen, and Wong. Acquisition of data: C. Chen,
X. Y. Chen, Soo, Leung, and Mok. Analysis and interpre-
tation of data: Wang, C. Chen, X. Y. Chen, Han, and Wong.
Drafting of the manuscript: Wang, X. Y. Chen, and Soo.
Critical revision of the manuscript for important intellec-
tual content: Wang, C. Chen, X. Y. Chen, Han, Leung, Mok,
and Wong. Statistical analysis: Wang, X. Y. Chen, Soo,
Leung, and Wong. Obtained funding: C. Chen. Study su-
pervision: Wong.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was supported by the Clini-
cal Effectiveness Unit of the Hospital Authority in Hong
Kong; grant NMRC/0691/2002 from the National Medi-
cal Research Council of Singapore; and the Clinical Trials
and Epidemiology Research Unit, Singapore. We also ac-
knowledge the S. H. Ho Cardiovascular Disease and Stroke
Center, Institute of Vascular Medicine, Chinese Univer-
sity of Hong Kong. Sanofi Aventis Singapore and
GlaxoSmithKline provided free samples of nadroparin for
patients in Singapore.
Role of the Sponsors: The funding sources had no role
in the design and conduct of the study; in the collec-
tion, analysis, and interpretation of the data; or in the
preparation, review, or approval of the manuscript.
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