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Review article Anticoagulant therapy for ischemic stroke:

A review of literature
Mohammad Mehdi Shahpouri1, Seyed Ali Mousavi1,2, Faribourz Khorvash1,2,
Seyed Morteza Mousavi2, Tahereh Hoseini2

1 2
Department of Neurology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. Isfahan Neurosciences
Research Center, Isfahan, Iran

For many years, anticoagulants have been used in the emergent treatment of patients with acute ischemic stroke. Anticoagulants are
prescribed in an effort to prevent first or recurrent stroke, especially among patients with cardioembolism due to arterial fibrillation
and large-artery atherosclerotic disease. Despite the widespread use, efficacy and safety of anticoagulants are controversial. Experts
have given a broad spectrum of opinions. Surveys of practitioners have also demonstrated a lack of consensus on the use of anticoa-
gulants for ischemic stroke. The uncertainty is due, in large part, to the lack of definitive clinical data. A review by the panel of the
Stroke Council of the American Heart Association found no strong evidence for effectiveness of anticoagulants in treating acute
ischemic stroke. Several clinical trials have suggested that utility of emergent anticoagulation has no significant effect in improving
clinical outcomes for patients with acute ischemic stroke. In the present review, we have attempted to provide a framework for the
emergent use of anticoagulants in acute ischemic stroke patients.

Key words: Ischemic Stroke, Anticoagulants, Significant effect

INTRODUCTION
and low molecular weight (LMW) heparin have
Stroke is the leading cause of disability and the been evaluated for the treatment of acute ischemic
third leading cause of death in the United States stroke. However, clinical trials have not adequately
with an estimated annual total cost of 57.9 billion evaluated adjusted‐dose intravenous anticoagula‐
dollars.[1] Each year, 5 million people die as a conse‐ tion in patients with selected stroke subtypes, and
quence of stroke, and at least 1 in 6 patients who only one trial has evaluated the role of very early
survive a stroke will suffer another stroke within 5 anticoagulation after stroke onset.[5] Beside uncer‐
years. There are about 600,000 new strokes each tainty regarding efficacy, a safety concern that ur‐
year in the European Union (EUSI 2003) and over gent anticoagulation may lead to symptomatic in‐
700,000 new strokes each year in the USA (AHA tracranial hemorrhage exists as well. Physicians
2006). Two‐thirds of all strokes occur in developing have been uncertain about the severity of neurolog‐
countries and over 80% of all stroke‐related deaths ical impairments or the initial CT findings that
occur in developing countries.[2] Although data on would contraindicate the early use of heparin. Anti‐
the epidemiology of stroke, its pattern and risk fac‐ coagulants often are prescribed to patients with re‐
tors from Iran is scarce, the available data suggests cent stroke in an effort to prevent early recurrent
relatively low incidence of stroke. This may reflect a stroke and to improve neurological outcomes. The
similarity toward neighboring countries and a con‐ Cerebral Embolism Study Group estimated that the
trast with Western countries.[3] risk of early recurrent embolism was 12% among
untreated patients with embolic stroke.[6,7] A Nor‐
Physicians have used anticoagulants to treat pa‐ wegian trial testing urgent anticoagulation among
tients with acute ischemic stroke for 50 years. These patients with recent stroke and atrial fibrillation
medications continue to be prescribed commonly. found the risk of recurrent stroke to be 8% in 1
Despite their widespread use, the usefulness of week.[8] Other trials testing anticoagulants in stroke
emergency anticoagulation is a subject of debate.[4] have found the rates of early recurrent stroke to be
Disagreements exist about the best agent to admi‐ much lower (in the range of 0.3%/d to 0.5%/d).[9‐11]
nister, the route of administration, the use of a bolus These relatively low rates mean that detection of a
dose to start treatment, the level of anticoagulation therapeutic effect in prevention of early recurrent
required, and the duration of treatment. Heparin stroke by anticoagulation will be difficult.

Address for correspondence: Seyed A Mousavi, Department of Neurology, Isfahan University of Medical Sciences, Isfahan, Iran.
E-mail: a_mousavi@med.mui.ac.ir
Received: 05-07-2011; Revised: 25-12-2011; Accepted: 05-01-2012

396 Journal of Research in Medical Sciences | April 2012 |


Shahpouri, et al. Anticoagulant therapy for ischemic stroke

There is substantial variability in the acute manage‐ acute performance of carotid duplex imaging to identi‐
ment of stroke within and between countries. Stroke fy patients with carotid occlusion or severe stenosis
clinicians are interested in studying variations in man‐ may improve selection of patients who could benefit
agement, because this may help them choose better from use of this agent.[19]
treatments that could improve outcomes.[12]
The FISS‐tris trial evaluated the LMW heparin nadro‐
Pathophysiology of Ischemic Stroke parin (3800 anti‐factor Xa international units, 0.4 ml
Approximately 45% of ischemic strokes are caused by subcutaneously twice daily) versus aspirin (160 mg
small or large artery thrombus, 20% are embolic in ori‐ once daily) started within 48 h of acute ischemic stroke
gin, and others have an unknown cause.[13] Thrombosis onset and continued for 10 days.[20] The main study
is the basic process in atherothrombotic ischemic population was 353 patients with confirmed large ar‐
stroke, and it can form in the extracranial and intra‐ tery occlusive disease, consisting of 300 with intra‐
cranial arteries when the intima is roughened and pla‐ cranial, 11 with extracranial, and 42 with both intra‐
que forms along the injured vessel. The endothelial cranial and extracranial disease. The mean time to
injury initiates platelet adhesion and aggregation, treatment was about 30 h. There was no significant dif‐
which is responsible for thrombus formation at the site ference between treatment with nadroparin or aspirin
of plaque. During an embolic stroke, a clot travels from for the proportion of patients with good outcome at six
a distant source and lodges in cerebral vessels. Micro‐ months (73% vs. 69% absolute risk reduction 4%; 95%
emboli can break away from sclerosed plaque in the CI ‐5 to 13).
artery or from cardiac sources such as atrial fibrillation,
patent foramen ovale, or a hypokinetic left ventricle.[13] In a trial of unfractionated heparin in hyperacute
Emboli in the form of blood, fat, or air can occur dur‐ stroke, a single center randomly assigned 418 patients
ing surgical procedures, most commonly during car‐ with nonlacunar hemispheric infarction (with car‐
diac surgery, but also after long bone surgeries.[14] Less dioembolic, atherothrombotic, or unknown/ undeter‐
common causes of ischemic stroke include carotid dis‐ mined etiology) to receive either intravenous heparin
section and the presence of coagulopathies.[15] Other or saline within 3 h of stroke onset for five days.[21] The
causes include arteritis, infection, and drug abuse, such primary endpoint (a favorable outcome at 90 days) was
as the use of cocaine.[13,16] As a thrombosis or emboli observed significantly more frequent in patients in he‐
cause a decrease in blood supply to the brain tissue, parin group as compared with those in saline group
events occur at the cellular level, referred to as the (38.9% vs. 28.6%, respectively, P = 0.025). Heparin use
ischemic cascade.[17] Understanding the ischemic cas‐ was associated with an increased risk of intracranial
cade has led to the concept of therapeutic time window and extracranial hemorrhage, with no significant in‐
for treatment possibilities.[18] crease in mortality. Other studies of heparin therapy in
acute stroke did not consider the etiology of stroke and
Anticoagulants Therapy for Stroke yielded mixed results.[21‐23]
Subtypes
As noted above, clinical trials have not adequately eva‐ Atrial Fibrillation and Cardioembolic
luated adjusted intravenous anticoagulation in patients Stroke
with selected stroke subtypes. Therefore, there are con‐ A subject of intense debate is the role of immediate
flicting data regarding the benefit of intravenous un‐ anticoagulation with heparin in stroke patients with
fractionated heparin or LMW heparin in the subgroup atrial fibrillation (AF). It appears that early treatment
of patients with large vessel atherosclerotic disease. with heparin in patients with AF who have an acute
The TOAST trial evaluated the efficacy of the LMW stroke may result in unfavorable clinical outcomes,
heparinoid danaparoid administered as an intravenous although a careful assessment of risk for thromboem‐
bolus within 24 h of symptom onset and continued for bolism and serious bleeding in individual patients is
seven days in 1281 patients with acute ischemic essential. Further evidence comes from a 2007 meta‐
stroke.[9] Compared to placebo, danaparoid was asso‐ analysis that examined seven trials involving 4624 pa‐
ciated with no improvement in overall outcome at tients and compared heparin with LMW heparins
three months (75% and 74%). However, subgroup started within 48 h of acute cardioembolic stroke with
analysis suggested a higher rate of favorable outcomes other treatments (aspirin or placebo).[24] The following
in patients treated with danaparoid who had a large observations were reported: 1) Anticoagulants were
artery atherosclerotic stroke (68% vs. 55% with place‐ associated with a statistically insignificant reduction in
bo). A subsequent analysis of this study suggested that recurrent ischemic stroke within 7 to 14 days (3.0% vs.

| April 2012 | Journal of Research in Medical Sciences 397


Shahpouri, et al. Anticoagulant therapy for ischemic stroke

4.9%, OR: 0.68, 95% CI: 0.44‐1.06). 2) Anticoagulants were assessed with sufficient data for comparison of
were associated with a statistically significant increase antiplatelet versus anticoagulation therapy.[32] In this
in symptomatic intracranial hemorrhage (2.5% vs. assessment, no randomized trials were identified, but
0.7%, OR: 2.89, 95% CI: 1.19‐7.01). 3. Anticoagulants 34 non‐randomized studies including 762 patients
and other treatments had a similar rate of death or dis‐ were evaluated. There was no significant difference in
ability at 3 to 6 months of follow up. Thus, the pub‐ risk of death [antiplatelet 5/268 (1.8%), anticoagulation
lished results do not support early anticoagulant 9/494 (1.8%), P = 0.88)]; stroke [(antiplatelet 5/268
treatment of acute cardioembolic stroke.[24] However, (1.9%), anticoagulant 10/494 (2.0%), P = 0.66)], or stroke
the use of warfarin is strongly recommended for pa‐ and death between antiplatelet and anticoagulatant
tients with left ventricular dysfunction and atrial fibril‐ therapy. There are no data to support the therapeutic
lation as it has been shown that atrial fibrillation is as‐ superiority of anticoagulants over antiplatelet agents
sociated with relatively high incidence of cardioembol‐ on treatment of cervical artery dissection.
ic events including stroke.[25] Warfarin can reduce the
risk of stroke in patients with atrial fibrillation. On the Venous Thrombus
other hand, the use of warfarin in patients with left Dural sinus and/or cerebral veins thrombosis (CVT) is
ventricular dysfunction and sinus rhythm is still a mat‐ an uncommon form of stroke, usually affecting young
ter of debate. The comparison between warfarin and individuals.[33,34] Anticoagulation therapy in CVT is
aspirin in the patients with reduced cardiac ejection used for prevention of thrombus growth, to facilitate
fraction (WARCEF) is currently underway.[26] recanalization, and to prevent DVT or PE. Controversy
has ensued because cerebral infarction with hemorr‐
Progressing Stroke hagic transformation or ICH is commonly present at
Heparin is often prescribed for patients who continue the time of diagnosis of CVT, and it may also compli‐
to have neurologic deterioration in the first hours or cate treatment.[35] Despite using anticoagulation in
days after stroke (i.e., “progressing stroke”, also re‐ treatment of patients with CVT there are controversies
ferred to as “stroke in evolution”). Studies performed due to complications such as hemorrhage conversion
in the 1950s and 1960s suggested that IV heparin ther‐ after ischemic stroke or ICH that may further compli‐
apy may be beneficial for patients with unstable cate the treatment plan.[35] Data from a meta‐analysis
ischemic stroke with as much as a 50% reduction in the that examined two trials revealed a statistically insigni‐
likelihood of further worsening.[27,28] These studies, ficant relative risk of death or dependency with anti‐
however, were either not randomized or blinded, had coagulation (RR: 0.46, 95% CI: 0.16‐1.31), with a risk
poorly defined inclusion and exclusion criteria, or did difference in favor of anticoagulation of 13% (95% CI:
not use standardized assessments for outcomes. Other 30%‐3%). The RR for death was 0.33 (95% CI: 0.08‐
nonrandomized studies of consecutive patients with 1.21).[36‐38] Another randomized trial included 57 wom‐
unstable stroke who received IV heparin have shown en with puerperal CVT confirmed by CT imaging.
high rates (27% to 50%) of further progression despite Treatment was with subcutaneous heparin 5000 IU
treatment.[29,30] The TOAST trial did not find an im‐ every 6 h, dose‐adjusted to an activated partial throm‐
provement in outcomes with danaparoid treatment in boplastin time 1.5 times baseline for at least 30 days
such patients, nor did a nonrandomized study of hepa‐ after delivery. Outcome assessment was not blinded.
rin therapy.[9] These findings do not support a role for Three patients in the control group either died or had
heparin in halting neurologic worsening after stroke. residual paresis compared with none in the heparin
So the 8th edition of American College of Chest Physi‐ group.[39] Other studies have suggested low rates of
cians (ACCP) Evidence Based Clinical Practice Guide‐ cerebral hemorrhage after anticoagulation for CVT.[36,40]
lines for Antithrombotic and Thrombolytic Therapy for The largest observational study was the ISCVT, which
Ischemic Stroke recommend against full dose anticoa‐ included 624 patients at 89 centers in 21 countries.
gulation for these patients.[31] Nearly all patients were treated with anticoagulation
initially, and mortality was 8.3% over 16 months; 79%
Cervical Artery Dissection had complete recovery (modified Rankin scale [mRS]
Cervical dissection is an important cause of stroke in score of 0 to 1), 10.4% had mild to moderate disability
the young. In a systematic review and meta‐analysis, (mRS score 2 to 3), and 2.2% remained severely dis‐
the effectiveness of different treatment approaches abled (mRS score 4 to 5).[41] Data from other observa‐
such as antithrombotic medications, thrombolysis and tional studies suggest a range of risks for ICH after
stenting in management of cervical arteries dissection anticoagulation for CVT from zero to 5.4%.[36,42‐44]

398 Journal of Research in Medical Sciences | April 2012 |


Shahpouri, et al. Anticoagulant therapy for ischemic stroke

Although there is limited data from randomized con‐ (22,125 patients), anticoagulants did not reduce the
trolled clinical trials, these findings, in combination odds of being dead or dependent at the end of follow‐
with observational data on outcomes and bleeding up (odds ratio 0.99, 95% CI 0.93‐1.04). 3) Although full
complications of anticoagulation, support a role for anticoagulant therapy was associated with about nine
anticoagulation in treatment of CVT, regardless of the fewer recurrent ischemic strokes per 1000 patients
presence of pretreatment ICH, and anticoagulation treated, it was also associated with a nine per 1000 in‐
appears safe and effective in CVT. Also, if anticoagula‐ crease in symptomatic intracranial hemorrhages. Simi‐
tion is given, there are no data supporting differences larly, anticoagulants avoided about four pulmonary
in outcome with the use of UFH in adjusted doses or emboli per 1000, but this benefit was offset by an extra
LMWH in CVT patients. nine major extracranial hemorrhages per 1000. 4) Sensi‐
tivity analyses did not identify a particular type of an‐
Heparin, LMW Heparin, and Warfarin ticoagulant regimen or patient characteristic associated
There are scant clinical data directly comparing unfrac‐ with net benefit.
tionated heparin with low molecular weight (LMW)
heparin for ischemic stroke treatment. One rando‐ A 2002 systematic review assessed the effectiveness of
mized, open‐label study of acute ischemic stroke pa‐ anticoagulants compared with antiplatelet agents in
tients found no significant difference between treat‐ acute ischemic stroke.[48] The reviewers concluded that
ment with intravenous heparin as compared with sub‐ anticoagulants offer no net advantages over antiplate‐
cutaneous enoxaparin twice daily.[45] Systemic and ce‐ let agents and they recommended that antiplatelet
rebral embolic events, bleeding complications, and agents be the antithrombotic agents of first choice.
outcome at three months were similar in both groups. However, this conclusion was driven in part by the
Another trial found that subcutaneous enoxaparin was lack of randomized trials comparing anticoagulation
as safe and effective as unfractionated heparin for pre‐ with antiplatelet therapy in the high‐risk settings
vention of venous thrombosis in acute ischemic stroke where we believe anticoagulation should be consi‐
patients.[46] dered.

The largest randomized controlled trial, which was Contraindications


performed in England and studied two doses of subcu‐ Anticoagulant therapy for acute stroke may only be
taneous heparin in undefined stroke patients, showed considered after a brain imaging study has excluded
no significant benefit with heparin.[10] LMW heparins hemorrhage and estimated the size of the infarct. Early
have several potential advantages over unfractionated anticoagulation should be avoided when potential con‐
heparin including ease of administration, more rapid traindications to anticoagulation are present, such as a
achievement of therapeutic effect, decreased require‐ large infarction (based upon clinical syndrome or brain
ments for blood testing (LMW heparins do not require imaging findings), uncontrolled hypertension, or other
PTT monitoring in patients who are not pregnant), and bleeding conditions. Although there is no standard
lower rates of thrombocytopenia. One disadvantage is definition, many stroke experts consider large infarcts
that LMW heparins are more expensive, although this to be those that involve more than one‐third of the
may be outweighed by reduced administration and middle cerebral artery territory or more than one‐half
monitoring costs. of the posterior cerebral artery territory based on neu‐
roimaging with CT or MRI.[49] Infarct size can also be
A systematic review published in 2008 examined the clinically defined, but this process can result in unde‐
effect of anticoagulant therapy versus control in the restimation of the true infarct volume when the so‐
early treatment of patients with acute ischemic called silent areas of the association cortex are in‐
stroke.[47] This review included 24 trials involving volved. Clinical estimation of infarct size should be
23,748 subjects. The quality of the trials varied consi‐ considered in conjunction with the National Institutes
derably. The anticoagulants tested were standard un‐ of Health Stroke Scale (NIHSS) score. One study found
fractionated heparin, low‐molecular‐weight heparins, that an NIHSS score greater than 15 was associated
heparinoids, oral anticoagulants, and thrombin inhibi‐ with a median infarct volume of 55.8 cm3 and worse
tors. The following were the major findings: 1) Based outcome than NIHSS scores of 1 to 7 (median volume
upon 11 trials (22,776 patients), anticoagulant therapy of 7.9 cm3) or 8 to 15 (median volume of 31.4 cm3).[50]
did not reduce the odds of death from all causes (odds Thus, patients with an NIHSS score >15 generally have
ratio 1.05, 95% CI 0.98‐1.12). 2) Based upon eight trials a large infarct. However, it should be recognized that,

| April 2012 | Journal of Research in Medical Sciences 399


Shahpouri, et al. Anticoagulant therapy for ischemic stroke

in the early hours of an acute stroke, part of the clinical after acute ischemic stroke: A randomized controlled trial. JA-
MA 1998;279:1265-72.
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Guidelines issued in 2007 by the American Heart Asso‐ CAST: Randomized placebo-controlled trial of early aspirin use
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