Thromboprophylaxis and early antithrombotic therapy in patients with acute ischemic stroke and cerebral venous and sinus thrombosis.

Abstract

So far, neither treatment with standard unfractionated heparin (UFH) nor with low-molecular-weight heparin (LMWH) has been shown to reduce mortality or to improve neurological outcome in patients with acute ischemic stroke. Although a reduction of early recurrent stroke has been demonstrated for the use of subcutaneous UFH, this benefit was offset by a similar-sized increase in hemorrhagic stroke. Double-blinded studies of LMWH have demonstrated no difference between active treatment and placebo suggesting that LMWH is not effective for the early secondary prevention of ischemic stroke. Although UFH and LMWH may be beneficial in certain subgroups of stroke who are at high risk for early stroke recurrence, these subgroups are still to be defined. Currently, low-dose UFH and LMWH can only be recommended for prophylaxis of deep vein thrombosis in patients with acute ischemic stroke with impaired mobility or other factors determining a particular high risk of venous thromboembolism. Available treatment data from controlled trials favor the use of anticoagulation as the first-line therapy for patients with cerebral venous and sinus thrombosis because it may reduce the risk of a fatal outcome and severe disability and does not promote intracranial hemorrhage.

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EUROPEAN JOURNAL OF MEDICAL RESEARCH 199
Abstract: So far, neither treatment with standard
unfractionated heparin (UFH) nor with low-mo-
lecular-weight heparin (LMWH) has been shown
to reduce mortality or to improve neurological
outcome in patients with acute ischemic stroke.
Although a reduction of early recurrent stroke has
been demonstrated for the use of subcutaneous
UFH, this benefit was offset by a similar-sized in-
crease in hemorrhagic stroke. Double-blinded
studies of LMWH have demonstrated no differ-
ence between active treatment and placebo sug-
gesting that LMWH is not effective for the early
secondary prevention of ischemic stroke. Although
UFH and LMWH may be beneficial in certain sub-
groups of stroke who are at high risk for early
stroke recurrence, these subgroups are still to be
defined. Currently, low-dose UFH and LMWH
can only be recommended for prophylaxis of deep
vein thrombosis in patients with acute ischemic
stroke with impaired mobility or other factors de-
termining a particular high risk of venous throm-
boembolism. Available treatment data from con-
trolled trials favor the use of anticoagulation as the
first-line therapy for patients with cerebral venous
and sinus thrombosis because it may reduce the
risk of a fatal outcome and severe disability and
does not promote intracranial hemorrhage.
Key words: ischemic stroke; anticoagulation; cere-
bral venous thrombosis; outcome
INTRODUCTION
Antithrombotic therapy is a crucial part of mod-
ern treatment of ischemic stroke, including anti-
platelet agents and anticoagulants in acute stroke
and in the long-term prevention of stroke recur-
rence. While oral anticoagulants have an estab-
lished role in the secondary prevention of cardi-
oembolic stroke, early anticoagulation with hep-
arin in the acute stage of ischemic stroke remains
controversial. Potential benefits of early anticoag-
ulant therapy include the improvement of stroke
outcome, the reduction of early stroke recurrence
and the prophylaxis of deep vein thrombosis
(DVT) and pulmonary embolism (PE) in immobi-
lized patients. However, these beneficial effects
may be counterbalanced by a substantial increase
of severe bleeding complications, particularly
intracranial hemorrhage.
Studies in the prevention and therapy of venous
thromboembolism (VTE) and in patients with
acute coronary syndromes have shown that low-
molecular-weight heparins
(LMWH) are superior to standard unfractionated
heparin (UFH) as they caused less bleeding and
other serious adverse events (Cohen et al. 1997,
Geerts et al. 2001, Leizorovicz et al. 1992, Lensing
et al. 1995). This clinical difference between UFH
and LMWH is likely to be a result of differences
in their pharmacokinetic features and their mech-
anisms of action (Bath 1998). LMWH have a high-
er bioavailability, a longer half-life and a reduced
protein binding, thereby producing a more pre-
dictable anticoagulant effect and they can safely
be administered subcutaneously once or twice
daily without monitoring. Moreover, LMWH
have less antiplatelet activity than UFH and do
not increase vascular permeability which may also
contribute to a reduced risk of bleeding. Given
these pharmacological advantages over UFH,
LMWH may improve safety and efficacy of early
anticoagulant therapy in patients with acute is-
chemic stroke as well. Over the last couple of
years, numerous clinical trials have examined the
utility of early anticoagulant therapy with UFH
or LMWH in acute ischemic stroke. This review
presents their results and especially focuses on the
published evidence of LMWH use in patients with
acute ischemic stroke.
and heparinoids
EFFECT OF EARLY ANTICOAGULATION ON
STROKE MORTALITY AND STROKE-RELATED
MORBIDITY
So far, neither treatment with standard unfrac-
tionated heparin (UFH) nor with low-molecular-
weight heparin (LMWH) has been shown to re-
duce mortality or to improve neurological out-
come in patients with acute ischemic stroke. For
the use of UFH, the International Stroke Trial
(IST) reported a negative result (International
Stroke Trial Collaborative Group 1997). This ran-
domized and open trial included almost 20 000 pa-
April 30, 2004
Eur J Med Res (2004) 9: 199-206
©I. Holzapfel Publishers 2004
THROMBOPROPHYLAXIS AND EARLY ANTITHROMBOTIC THERAPY IN
PATIENTS WITH ACUTE ISCHEMIC STROKE AND CEREBRAL VENOUS
AND SINUS THROMBOSIS
M. Busch and F. Masuhr
Department of Neurology, Charité Medical School, Humboldt University, Berlin, Germany

Page 2

tients and studied the safety and efficacy of subcu-
taneous UFH and aspirin within 48 hours of
stroke onset in four different treatment groups:
(1) aspirin 300 mg daily, (2) heparin at two doses
(5000 or 12500 IU twice a day), (3) aspirin plus
heparin, and (4) no aspirin and no heparin which
were studied in a multifactorial design. Treatment
continued for 14 days and the primary outcomes
were death within 14 days and death and depen-
dency at 6 months. Heparin (low- and high-dose
group combined) treatment was associated with
non-significantly fewer deaths within 14 days
(9.0% heparin vs. 9.3% no heparin). At 6 months
the percentage of patients who were dead or de-
pendent was identical in both groups (62.9%). At
the same time, heparin was associated with a sig-
nificant excess of 9 transfused or fatal extracranial
bleeds per 1000 patients treated. Thus, UFH
showed no statistically significant benefit on the
primary outcomes, hence showing no beneficial
effect on the improvement of neurological out-
come or a reduction of mortality. Aspirin therapy
was also associated with only non-significantly
fewer deaths within 14 days (9.0% aspirin vs. 9.4%
no aspirin) but at 6 months the number of pa-
tients who had died or were dependent was (after
adjustment for baseline prognosis) significantly
lower in aspirin-allocated patients (14 per 1000
treated patients). Thus, aspirin showed a small but
worthwhile improvement at 6 months.
Six major trials of LMWH in acute ischemic
stoke have been published (see Table 1 for trial
characteristics). One small trial with nadroparine
(4100 anti-factor Xa IU twice a day versus 4100 IU
daily versus placebo within 48 hours of stroke
onset) reported a significant, dose-dependent ben-
efit with a better clinical outcome (death or de-
pendency) 6 months after the stroke in patients re-
ceiving the high-dose with no significant increase
in the rate of hemorrhagic complications (Kay et
al. 1995). However, a larger European study could
not confirm this beneficial effect of nadroparine
(Hommel et al. 1998). Further prospective out-
come studies with LMWH failed to show any dif-
ference in functional outcome in the treated
groups compared with placebo (Moonis and
Fisher 2002). The TOAST trial randomized 1281
patients with acute stroke within 24 hours after
onset of symptoms to receive either the low-mo-
lecular-weight heparinoid danaparoid or placebo
(The Publications Committee for the TOAST
Investigators 1998). Main outcome measure was a
favorable outcome at 3 months or 7 days rated as
the combination of a Glasgow Outcome Score of
1 or 2 and a modified Barthel Index of 12 or great-
er (on a scale of 0 to 20). Although there was a sig-
nificant benefit for the active treatment group
after seven days, this difference was not statistical-
ly significant after 3 months (which was the pri-
mary outcome time point of the study) with
75.2% of the danaparoid group and 73.7% of the
placebo group having favorable outcomes (p =
0.49). There were significantly more symptomatic
intracerebral hemorrhages in the active treatment
arm (2.3% vs. 0.8%).
The TOPAS trial was a dose-finding study
which compared 4 different doses of certoparin
(3000 U anti-factor Xa once daily, 3000 U twice
daily, 5000 U twice daily and 8000 U twice daily)
given within 12 hours of stroke onset in a total of
404 patients (Diener et al. 2001). The trial includ-
ed no placebo group. There was no correlation
between the dose of certoparin and an improve-
ment of neurological or functional outcome at 3
months. Severe bleeding tended to be more fre-
quent in the highest dose group only. The TAIST
study randomized 1486 patients with acute is-
chemic stroke to receive either high-dose tinzapar-
in (175 anti Xa IU/kg), low-dose tinzaparin (100
anti Xa IU/kg), or 300 mg aspirin within 48 hours
EUROPEAN JOURNAL OF MEDICAL RESEARCH 200April 30, 2004
Table 1. Trials of LMWH in patients with acute ischemic stroke.
FISS FISS bisTOASTHAESTTOPASTAIST
LMWH nadroparinenadroparinedanaparoid dalteparincertoparintinzaparin
Dose (U anti-Xa)4100 once daily
4100 twice daily
85 U/kg once
daily
85 U/kg twice
daily
adjusted for
anti-Xa level
0.6 to 0.8
100 U/kg twice 3000 once daily
daily
100 U/kg once
daily
175 U/kg once
daily
3000 twice daily
5000 twice daily
8000 twice daily
Route of application s.c.s.c. i.v.s.c. s.c.s.c.
Controlplacebo placeboplacebo ASS-ASS
Patients (n) 312 7671281 450 8001486
Inclusion interval (h) 4824 2430 1248
Treatment period (d) 10 107 1014 10
Follow up (months)363336
Primary endpointdeath or
dependency
death or
dependency
GCS and
modified Barthel ischemic stroke
Barthel Index, Barthel Index modified Rankin
Scale
Reference Kay 1995 Hommel 1998 TOAST 1998Berge 2000Diener 2001 Bath 2001

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after symptom onset (Bath et al. 2001). The pri-
mary outcome measure (assessed with the modi-
fied Rankin scale) was independence, disability or
death at 6 months. The study found no difference
in outcome between the three treatment groups.
The HAEST trial was a randomized double-blind
study which compared the efficacy of dalteparin
(100 IU/kg subcutaneously twice daily) and aspi-
rin (160 mg daily) in patients with acute ischemic
stroke and atrial fibrillation (Berge et al. 2000).
Treatment was started within 30 hours of stroke
onset and continued for the first 14 days. At 3
months, there was no significant difference in out-
come. The percentage of death or dependency was
66.1% in patients allocated to dalteparin and
64.8% in patients allocated to aspirin. Dalteparin
was associated with a significantly higher frequen-
cy of extracerebral hemorrhages (5.8% vs. 1.8%).
Consistent with the results of these major trials
of UFH and LMWH in acute ischemic stroke, a
Cochrane systematic review based on twenty-one
trials involving 23,427 patients (Gubitz et al.
2004), found no net short- or long-term beneficial
effect on death or dependency associated with an
immediate therapy with UFH, LMWH, hepari-
noids or oral anticoagulants in patients with acute
ischemic stroke. Although a recent systematic re-
view focusing on trials of LMWH in acute ischem-
ic stroke observed a nonsignificant reduction in
combined death and disability in patients treated
with LMWH, this effect was again outweighed by
increases in case fatality and symptomatic intra-
cranial hemorrhage (Bath et al. 2000).
In conclusion, with the exception of one small
study no controlled trial and no meta-analysis has
yet demonstrated an improved outcome or a re-
duced mortality by UFH or LMWH therapy in
patients with acute ischemic stroke. Currently,
neither UFH nor LMWH can be recommended
for the treatment of stroke-related morbidity.
EFFECT OF ANTICOAGULATION ON EARLY
STROKE RECURRENCE AND IN DIFFERENT
STROKE SUBTYPES
Although treatment with UFH or LMWH does
not reduce stroke-related morbidity and mortal-
ity, anticoagulation may still be useful to prevent
early stroke recurrence. In the IST study (Inter-
national Stroke Trial Collaborative Group 1997),
patients allocated to subcutaneous UFH had sig-
nificantly fewer recurrent ischemic strokes within
the first 14 days (2.9% vs. 3.8%) but this beneficial
effect was offset by a similar-sized significant in-
crease in hemorrhagic strokes (1.2% vs. 0.4%). In
contrast, the significant decrease of recurrent
stokes among aspirin-allocated patients (2.8% vs.
3.9%) was not offset by an increase of hemorrhag-
ic strokes (0.8% vs. 0.9%). In the Cochrane sys-
tematic review of anticoagulants in patients with
acute stroke (Gubitz et al. 2004), immediate anti-
coagulant therapy was associated with about 9
fewer recurrent ischemic strokes per 1000 patients
treated. However, it was also associated with a
similar sized 9 per 1000 increase in symptomatic
intracranial hemorrhages.
Nevertheless, the increase in hemorrhagic
strokes among heparin-allocated patients in IST
should be viewed critically in regard to potential
pitfalls of the trial. Computed tomography (CT)
was not a requirement before study inclusion and
more than 30% of all patients were randomized
before a cerebral CT scan was obtained making it
likely that patients with hemorrhagic strokes
have been included. In addition, there was no
systematic coagulation monitoring and several pa-
tients, particularly those receiving 12500 IU twice
daily might have been outside the therapeutic
range. A prospective study of patients with large
cerebral embolic infarction receiving early antico-
agulation with intravenous heparin showed that
the risk of hemorrhagic worsening was signifi-
cantly related to excessive prolongation of the ac-
tivated partial thromboplastin time (aPPT). The
authors recommended a rigorous coagulation
monitoring to keep the aPTT at 1.5 to 2.0 times
control values (Chamorro et al. 1995). While high-
dose heparin was associated with a non-significant
increase in early death or recurrent stroke and a
definite excess of transfused or fatal extracranial
bleeds in the IST study, low-dose heparin was as-
sociated with a significant decrease of early death
or stroke (10.8% vs. 12.0%) without a significant
excess of transfused or severe extracranial bleeds
(International Stroke Trial Collaborative Group
1997).
Although the small overall reduction of recur-
rent ischemic stroke by heparin is offset by an
equal-sized increase of symptomatic hemorrhage
in general stroke populations, certain subtypes of
stroke may carry a higher risk of recurrence and
may benefit from early anticoagulant therapy.
This has been suggested for patients with cardi-
oembolic stroke and particularly for those with
atrial fibrillation (AF).
Oral anticoagulant therapy is an established
long-term prophylaxis of cerebral and systemic
embolism in AF. Several primary prevention
trials in patients with AF have shown that oral
anticoagulants like warfarin and phenprocoumon
reduce the risk of stroke by 60-70% (Atrial Fibril-
lation Investigators 1994). A prophylactic effect of
equal magnitude was found for long-term oral
anticoagulation after a stroke by a single secon-
dary prevention trial (EAFT 1993), but the best
time to start anticoagulant therapy could not be
estimated as in most patients effective anticoagula-
tion was obtained only weeks after their stroke.
However, patients with acute stroke and AF have
an increased risk of early recurrence which was es-
timated to be 10-20% within 14 days after stroke
onset in observational studies (Cerebral Embolism
Task Force 1989). In recent controlled stroke
trials however, early stroke recurrence was sub-
stantially lower and reached 5-8% in patients
treated with aspirin or placebo (Berge et al. 2000,
Saxena et al. 2001, The Publications Committee
for the TOAST Investigators 1998).
EUROPEAN JOURNAL OF MEDICAL RESEARCH April 30, 2004 201

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A first small randomized study that compared
intravenous UFH with no antithrombotic treat-
ment in 45 patients with cardioembolic stroke was
terminated prematurely after two strokes and two
hemorrhagic transformations had occurred in the
control group (Cerebral Embolism Study Group
1983). Later studies, however, could not unequiv-
ocally demonstrate a benefit of early anticoagula-
tion. In the International Stroke Trial, a total of
3169 patients with AF had been included and their
outcome has been reported separately (Saxena et al.
2001). Although a clear and dose-dependent reduc-
tion in early recurrent ischemic stroke among pa-
tients treated with subcutaneous UFH was found,
there was no net advantage to treatment with hep-
arin as the frequency of hemorrhagic strokes was
significantly increased and combined incidences of
ischemic stroke and intracranial hemorrhage were
about 5% in all treatment groups. In the HAEST
study, which evaluated the efficacy of the LMWH
dalteparin compared with aspirin in 449 patients
with acute ischemic stroke and AF, rates of recur-
rent ischemic stroke (8.5% vs. 7.5%, p = 0.73) and
frequencies of secondary brain hemorrhage (2.7%
vs. 1.8%, p = 0.54) were each not different between
treatment groups. Moreover, neither HAEST nor
IST showed a benefit of anticoagulation on func-
tional outcome or death in the subgroup of stroke
patients with AF. In addition, none of the other
trials of LMWH in acute stroke found a positive ef-
fect on these clinical endpoints in subgroups of pa-
tients with cardioembolic stroke (Berge et al. 2000,
Hommel et al. 1998, Kay et al. 1995, The Publicati-
ons Committee for the TOAST Investigators
1998). Thus, most authors come to the conclusion
that heparin should not routinely be used for early
anticoagulation in patients with AF and presumed
cardioembolic stroke (Berge et al. 2000, Hart et al.
2002, Saxena et al. 2001).
Under pathophysiologic considerations, how-
ever, anticoagulation may be feasible for certain
subgroups of stroke patients with presumed cardi-
oembolism who are at particularly high risk for
recurrence such as patients with mechanical heart
valves or recent myocardial infarction with mural
thrombi. Data regarding the relative risks and
benefits of anticoagulants in these patients are
lacking. Patients with dissection of the extracrani-
al carotid or vertebral arteries may also benefit
from early anticoagulation to prevent stroke re-
currence due to artery-to-artery embolism arising
from local thrombus formation at the site of dis-
section. Uncontrolled series showed a favorable
outcome of patients who received early heparin
treatment whereas those without suffered from se-
vere stroke due to embolic middle cerebral artery
occlusion (Sturzenegger 1995). The TOAST study
did find a significant response to treatment with
danaparoid at 7 days and 3 months among patients
with stroke due to large-artery atherosclerosis
which also suggests a possible benefit of anticoag-
ulants in the prevention of artery-to-artery embo-
lism. No benefit of danaparoid was observed
among patients with stroke due to small-artery oc-
clusion and unselected patients with presumed
cardioembolic stroke (The Publications Commit-
tee for the TOAST Investigators 1998).
In conclusion, the routine use of UFH or
LMWH to prevent early stroke recurrence cannot
be recommended in patients with acute ischemic
stroke. The reason for this negative recommenda-
tion is not only a general lack of proof of efficacy
but also safety concerns about an unacceptable in-
crease of severe bleeding complications, particular-
ly cerebral hemorrhage. If early anticoagulation is
initiated in a patient with a particular stroke sub-
type because of a pathophysiological rationale, the
risk of bleeding complications must be minimized.
This includes regular coagulation monitoring and
the routine use of CT scans with strict exclusion
of patients with hemorrhagic infarcts, large in-
farcts, and severe cerebral leukoaraiosis. Patients
with systemic contraindications such as severe un-
controlled hypertension, uncorrected bleeding dis-
orders or potential bleeding lesions should also
been excluded from early anticoagulation.
BRIDGING THERAPY FROM ACUTE TO
LONG-TERM ANTICOAGULATION
In clinical practice, it is a common proceeding to
start heparin therapy in the first days after a TIA
or a small cerebral infarct in patients with AF
while overlapping oral anticoagulant therapy has
not reached therapeutic INR levels. This proceed-
ing has been described as “bridging therapy from
acute to long-term anticoagulation” and a small
study of 48 patients has compared the risk-benefit
profiles of intravenous UFH and the LMWH
enoxaparin in this setting (Kalafut et al. 2000).
The authors found that fewer patients in the enox-
aparin group experienced neurological worsening
as compared with the UFH group (8% vs. 33%,
p<0.05) and that the rate of bleeding complica-
tions was lower. Moreover, the length of hospital
stay and the total cost of care were reduced for
enoxaparin treated patients. However, since all
large prospective trials of UFH and LMWH in
acute stroke and available meta-analyses have been
negative and risk of early recurrence is lower than
previously thought, the reasonability of a bridg-
ing therapy with any type of heparin must be
questioned. Until recently, bridging with heparin
was generally recommended because of the fear of
creating a hypercoagulable state in patients with
unrecognized protein C deficiency by starting
oral anticoagulation alone. However, this fear has
not been substantiated. Presently, to administer
heparin before or at the same time as oral antico-
agulants is only recommended in patients with a
known protein C deficiency or other thrombo-
philic state (Ansell et al. 2001).
PREVENTION OF VENOUS THROMBOEMBO-
LISM AFTER ISCHEMIC STROKE
Venous thromboembolism (VTE) is a common
complication and an important cause of death and
EUROPEAN JOURNAL OF MEDICAL RESEARCH 202April 30, 2004

Page 5

morbidity in acute ischemic stroke. Compared to
other medical conditions, patients with stroke are
at particularly high risk of VTE because of limb
paralysis, prolonged immobility and increased
prothrombotic activity. Deep vein thrombosis
(DVT) was found in about 50% of stroke patients
without prophylaxis in randomized trials using
venography, ultrasonography or fibrinogen leg
scanning (Geerts et al. 2001, Gubitz et al. 2004).
Pulmonary embolism (PE), the most serious con-
sequence of DVT, can result in significant mor-
bidity and has been estimated to be responsible
for approximately 5-13% of early deaths following
stroke (Geerts et al. 2001, Mazzone et al. 2004).
Several trials have demonstrated that both
UFH and LMWH are effective in reducing the
risk of VTE in stroke patients. Aside from those
trials which primarily studied outcome and stroke
recurrence after ischemic stroke, numerous small-
er studies specifically evaluated the efficacy of
UFH and LMWH in the prophylaxis of DVT in
patients with acute stroke. Pooled results of five
trials of low-dose UFH demonstrated a 56% rela-
tive risk reduction in DVT relative to pooled con-
trol patients (Geerts et al. 2001). Similarly, results
of three trials of LMWH showed a relative risk re-
duction in DVT of 58% for treated patients. In
two trials directly comparing enoxaparin 40mg
once daily to low-dose UFH, the LMWH enoxap-
arin provided greater protection from DVT with-
out increasing risk of hemorrhage, with relative
risk reductions favoring LMWH of 29% and 43%,
respectively (Geerts et al. 2001, Harenberg et al.
1999, Hillbom et al. 1999). The low-molecular-
weight heparinoid danaparoid was also effective in
DVT prophylaxis compared to placebo and there
was a relative risk reduction of 44% compared to
low-dose UFH in 2 trials (Dumas et al. 1994,
Geerts et al. 2001, Turpie et al. 1992).
All these studies on DVT prophylaxis after
stroke focused on thrombi detected by sensitive
diagnostic tests. However, most thrombi were
asymptomatic or not clinically relevant and more
major clinical endpoints like death, functional
outcome, symptomatic PE and severe hemorrhage
seem more appropriate for assessing the value of
anticoagulant therapy in prevention of VTE in
stroke patients (Geerts et al. 2001). Most of the al-
ready mentioned trials of heparin for the treat-
ment of acute ischemic stroke evaluated frequency
of VTE aside from major clinical endpoints. The
largest trial so far, the International Stroke Trial,
found a significant reduction in the frequency of
fatal and symptomatic non-fatal PE, with an inci-
dence of 0.8% in the non-treated group and 0.5%
in patients treated with subcutaneous UF
(p=0.02) (International Stroke Trial Collaborative
Group 1997). In another large scale randomised
trial which compared danaparoid with placebo,
none of the treated patients experienced clinical
significant VTE compared to an incidence of 0.4%
in the placebo group
Committee for the TOAST Investigators 1998).
However, in both trials heparin treatment did not
(The Publications
improve the overall outcome of patients with
acute ischemic stroke and at final follow up there
was no difference in the proportion of patients
dead or dependent as any reductions in recurrent
ischemic stroke or PE were counterbalanced by
similar-sized increases in intracranial and extracra-
nial hemorrhages. Trials of LMWH produced sim-
ilar results. In the only small trial that demon-
strated a beneficial effect of the LMWH nadropa-
rine on the clinical outcome of stroke patients at 6
months (FISS), frequencies of VTE were to low to
detect any relevant difference between treatment
groups (Kay et al. 1995) and the overall positive
effect of nadroparine was not confirmed in the
later FISS bis trial (Hommel et al. 1998). In two
recent outcome trials of LMWH in acute stroke,
there was no overall benefit on the primary clini-
cal endpoints (Bath et al. 2001, Berge et al. 2000).
Although no DVT occurred in patients treated
with high-dose tinzaparin in the TAIST trial (Bath
et al. 2001), this benefit was again offset by an in-
creased rate of intracerebral hemorrhage and over-
all there was no difference in PE, stroke recur-
rence, death and functional dependency between
patients treated with aspirin, high-dose and low-
dose tinzaparin. In the HAEST study on daltepar-
in in patients with acute stroke and AF (Berge et
al. 2000), the frequency of VTE was non-signifi-
cantly lower in the group of patients treated with
dalteparin (0.4% compared to 2.2% in patients
treated with aspirin, p=0.22), but more severe
hemorrhages occurred in the dalteparin group and
no effect on stroke recurrence and outcome was
found.
In the Cochrane systematic review of anticoagu-
lants in patients with acute stroke (Gubitz et al.
2004), treatment with UFH, LMWH, heparinoids
or oral anticoagulants was associated with a signifi-
cant reduction in DVT from 44% in controls to
15% in treated patients. The absolute reduction on
DVT with anticoagulation was substantial with
281 DVTs prevented per 1000 patients treated.
However, only 916 patients from 10 trials (3.9%
of all patients included) were systematically stud-
ied to determine the effect of anticoagulants on the
occurrence of symptomatic or asymptomatic DVT.
Moreover, anticoagulant therapy was also associat-
ed with a 9 per 1000 increase in symptomatic intra-
cranial hemorrhages. Similarly, anticoagulants
avoided about 4 pulmonary emboli per 1000, but
this benefit was offset by an extra 9 major extra-
cranial hemorrhages per 1000 treated patients.
Similar to the results of the Cochrane meta-
analysis, the recent systematic review focusing on
trials of LMWH in acute ischemic stroke by Bath
et al. found that LMWH therapy lowered the fre-
quency of DVT and symptomatic PE but in-
creased the risk of major extracranial bleeding
(Bath et al. 2000). In another Cochrane systematic
review of five small trials directly comparing
LMWH with UFH in patients with acute ischem-
ic stroke LMWH treatment decreased the occur-
rence of DVT from 22% to 13% but too few data
were available to provide a reliable estimate of
EUROPEAN JOURNAL OF MEDICAL RESEARCHApril 30, 2004 203

Page 6

more important clinical outcomes. However, the
existing data on LWMH in acute stroke are consis-
tent with results of studies in the prevention of
perioperative thrombosis and in the treatment of
DVT which also found LMWH to be superior to
UFH in terms of efficacy and safety (Geerts et al.
2001, Leizorovicz et al. 1992, Lensing et al. 1995).
On the grounds of trial results, treatment
guidelines and consensus statements recommend
both low-dose UFH and LMWH for DVT pro-
phylaxis only for those patients with acute is-
chemic stroke with impaired mobility or other
factors determining a particular high risk of VTE
(Adams et al. 2003, Geerts et al. 2001, The
European Stroke Initiative 2003). However, un-
like the missing benefit of both LMWH and UFH
on overall clinical outcome, data from several in-
dividual trials and meta-analyses suggest a super-
iority of LMWH over UFH with respect to DVT
prophylaxis which is reflected in the current clini-
cal praxis on German stroke units. In a recent
published survey on coagulation therapy in acute
stroke patients from all major stroke units in
Germany, the majority of participants reported to
use LMWH for prophylaxis of venous throm-
boembolism (Daffertshofer et al. 2003).
ANTICOAGULATION IN PATIENTS WITH CE-
REBRAL VENOUS AND SINUS THROMBOSIS
Anticoagulation has shown to be effective in the
treatment of patients with extracerebral venous
thrombosis and its use has also been advocated in
patients with cerebral venous thrombosis after the
first report of successful heparin therapy by
Stansfield in 1942. However, since intracranial
hemorrhage occurs in 30-50% of patients with ce-
rebral venous and sinus thrombosis (CVST),
many neurologists hesitated to use heparin be-
cause they feared that anticoagulation may either
promote intracranial hemorrhage or cause clinical
deterioration if intracranial hemorrhage is already
present. Since Stansfield`s initial publication,
there have been numerous reports of dramatic im-
provement in patients receiving anticoagulants
(for review see Einhäupl and Masuhr 1994) and
today there are data available from two controlled
trials which favor the use of anticoagulants in pa-
tients with CVST because it may reduce the risk
of a fatal outcome and severe disability and does
not promote intracranial hemorrhage (Einhäupl et
al. 1991, de Bruijn et al. 1999).
In the prospective study of Einhäupl and co-
workers which compared dose-adjusted intrave-
nous heparin with placebo in 20 patients, 8 pa-
tients in the heparin group recovered completely
and none died whereas only one patient in the pla-
cebo group recovered fully and 3 patients died.
Three patients with previous intracranial hemor-
rhage recovered completely and no new hemor-
rhages occurred in the heparin group whereas in
the placebo group 2 patients with pre-treatment
hemorrhage died and 2 new intracranial hemor-
rhages were observed.
The safety and good responsiveness of patients
with CVST to anticoagulant therapy even in the
presence of intracranial hemorrhage may be ex-
plained by the underlying
(Villringer et al. 1994). Venous thrombotic occlu-
sion causes an increase of venous and capillary
pressure which promotes the diapedesis of eryth-
rocytes into the brain parenchyma. Therefore,
persistence of thrombosis is the key mechanism of
CVST-related hemorrhage. Heparin therapy pre-
vents further propagation of thrombosis and re-
occlusion of recanalized (due to endogenous lysis)
venous vessels. Capillary pressure decreases after
recanalization which prevents further diapedesis
of erythrocytes. This may explain the reduction
of intracranial hemorrhage in patients with CVST
during heparin treatment (see Fig. 1).
The effectiveness of body weight adjusted low-
molecular-weight heparin has been studied in a
second randomized treatment trial (de Bruijn et al.
1999). The authors compared nadroparine (180
anti Xa U/kg per 24 hours administered by 2
daily subcutaneous injections) with placebo in 60
patients with CVST. A poor outcome - defined as
death or Barthel index <15 - was observed after 3
weeks in 6 of the 30 patients treated with LMWH
(20%) compared to 7 of the 29 controls (24%).
After 12 weeks, 3 patients (10%) in the LMWH
group and 6 patients (21%) in the placebo group
had a poor outcome which corresponded to a non-
significant absolute risk reduction of 11% in favor
of the active treatment. No new intracranial hem-
orrhages or secondary worsening of the 15 pa-
tients with pre-treatment hemorrhage were ob-
served in the LMWH group. A meta-analysis of
the two therapy trials (de Bruijn et al. 1999)
showed that the use of anticoagulants led to an ab-
solute risk reduction in mortality of 14% and in
death or dependency of 15% with relative risk re-
ductions of 70% and 56%, respectively. Although
this difference was not statistically significant
(presumably due to the small sample size with a
total of 79 patients) both trials showed a consis-
tent and clinically meaningful trend in favor of
anticoagulation and demonstrated the safety of
anticoagulant therapy.
In conclusion, the available data reinforce the
use of heparin as first-line treatment of CVST.
However, it is unclear, whether treatment with
full-dose intravenous heparin or subcutaneously
applied LMWH is equally effective since there is
no study which has compared these two treatment
regimes. We recommend the use of intravenous
heparin in critical ill patients because the aPTT
may normalize within 1 h after discontinuation of
the infusion if complications occur or surgical
intervention is necessary. However, in less severe
cases (e.g. ambulatory patients) treatment with
subcutaneously applied LMWH may be feasible.
pathophysiolgy
CONCLUSION
Currently, all patients with acute ischemic stroke
should receive aspirin to reduce stroke-related
EUROPEAN JOURNAL OF MEDICAL RESEARCH204 April 30, 2004

Page 7

morbidity and mortality unless there are contrain-
dications such as allergy and gastrointestinal
bleeding. The use of UFH or LMWH cannot be
recommended except for the prevention of deep
vein thrombosis in patients with impaired mobil-
ity or other factors determining a high risk for ve-
nous thromboembolism if risk of bleeding is mini-
mized. In such patients, the concurrent use of
low-dose LMWH and aspirin may be a feasible op-
tion and is already the preferred therapeutic con-
cept on most German stroke units (Daffertshofer
et al. 2003). Further clinical research should aim
at the identification of stroke subgroups who
carry a particular high-risk for stroke recurrence
and may benefit from early anticoagulation with
UFH or LMWH.
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Address for correspondence:
Dr. med. Florian Masuhr
Department of Neurology
Charité Medical School
Humboldt-University
Schumannstrasse 20/21
D-10117 Berlin, Germany
Phone: +49-30-450 560074
Fax: +49-30-450 560932
E-mail: Florian.Masuhr@charite.de
EUROPEAN JOURNAL OF MEDICAL RESEARCH206 April 30, 2004