BEST 2009 Stroke Management

Stroke management
Search date June 2009

Josef Alawneh, Philip Clatworthy, Rhiannon Morris, and Elizabeth Warburton
ABSTRACT
INTRODUCTION: Stroke is the third most common cause of death in most developed countries. It is a worldwide problem; about 4.5 million
people die from stroke each year. Stroke can occur at any age, but half of all strokes occur in people aged over 70 years. About 80% of all
acute strokes are ischaemic, usually resulting from thrombotic or embolic occlusion of a cerebral artery. The remainder are caused either
by intracerebral or subarachnoid haemorrhage. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer
the following clinical questions: What are the effects of specialised care in people with acute stroke? What are the effects of medical treatment
in people with acute ischaemic stroke? What are the effects of decompressive hemicraniectomy in acute ischaemic stroke? What are the
effects of surgical evacuation for intracerebral haematomas? We searched: Medline, Embase, The Cochrane Library, and other important
databases up to June 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version
of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK
Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 44 systematic reviews, RCTs, or observational
studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In
this systematic review we present information relating to the effectiveness and safety of the following interventions: acute reduction in blood
pressure, aspirin, evacuation (early surgical evacuation, or conservative treatment), decompressive hemicraniectomy, neuroprotective agents
(calcium channel blockers, citicoline, gamma-aminobutyric acid agonists, glycine antagonists, lubeluzole, magnesium, N-methyl-D-aspartate
antagonists), specialised stroke care, systemic anticoagulation (heparinoids, low or specific thrombin inhibitors, low molecular weight heparin,
oral anticoagulants, unfractionated heparin), and thrombolysis.
QUESTIONS
What are the effects of specialised care in people with acute stroke?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
What are the effects of medical treatment in people with acute ischaemic stroke?. . . . . . . . . . . . . . . . . . . . . . . 4
What are the effects of decompressive hemicraniectomy in acute ischaemic stroke?. . . . . . . . . . . . . . . . . . . . 14
What are the effects of surgical evacuation for intracerebral haematomas?. . . . . . . . . . . . . . . . . . . . . . . . . . . 15
INTERVENTIONS
SPECIALISED CARE IN STROKE
Beneficial
Specialised care (specialist stroke rehabilitation) . . . 3
MEDICAL TREATMENT IN ACUTE ISCHAEMIC
STROKE
Beneficial
Aspirin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Trade off between benefits and harms
Systemic anticoagulation (unfractionated heparin or
LMWH) may be similarly effective to aspirin at reducing
death or dependency following stroke, but are associated
with increased risk of intracranial haemorrhage. . . . 5
Thrombolysis (increased overall mortality and fatal
haemorrhages but reduced combined death or depen-
dency; beneficial effects on death or dependency do not
extend to streptokinase) . . . . . . . . . . . . . . . . . . . . . . 7
Unlikely to be beneficial
Acute reduction in blood pressure . . . . . . . . . . . . . 13
Neuroprotective agents (calcium channel blockers, citi-
coline, GABA agonists, glycine antagonists, lubeluzole,
magnesium, N-methyl-D-aspartate antagonists) . . . 9
SURGERY: DECOMPRESSIVE HEMICRANIECTOMY
Likely to be beneficial
Decompressive hemicraniectomy New . . . . . . . . . 14
SURGERY: EVACUATION OF INTRACEREBRAL
HAEMATOMA
Trade off between benefits and harms
Evacuation (evidence of benefit for supratentorial
haematomas; insufficient evidence in infratentorial
haematomas) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
To be covered in future updates
Other treatments for acute ischaemic stroke (corticos-
teroids, fibrinogen-depleting agent, glycerol, haemodilu-
tion techniques, mannitol)
Preventing deep venous thrombosis/pulmonary em-
bolism in people with stroke using aspirin or compression
stockings
Key points
Stroke is characterised by rapidly developing clinical symptoms and signs of focal, and at times global, loss of
cerebral function lasting over 24 hours or leading to death, with no apparent cause other than that of vascular origin.
Ischaemic stroke (which accounts for about 80% of all acute strokes) is caused by vascular insufficiency (such
as cerebrovascular thromboembolism) rather than haemorrhage.
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BMJ Publishing Group Ltd 2010. All rights reserved. . . . . . . . . . . . . . . . . . . . . . 1 . . . . . . . . . . . . . . . . . . . . . Clinical Evidence 2010;04:201
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
It is the third most common cause of death in most developing countries, with about 4.5 million people worldwide
dying from stroke each year.
About 10% of all people with acute ischaemic strokes will die within 30 days of onset, and, of those who survive
the acute event, about 50% will still experience some level of disability after 6 months.
Specialised stroke rehabilitation seems more effective than conventional care at reducing death and dependency
after 1 year.
Aspirin effectively reduces death or dependency at 6 months when given within 48 hours of ischaemic stroke.
Aspirin has a similar effectiveness as anticoagulants (unfractionated or low molecular weight heparin), but a
lower risk of intra- and extracranial haemorrhage.
Thrombolysis (given within 3 hours of symptom onset) reduces death or dependency at 6 months in people with
confirmed ischaemic stroke, but increases the risk of symptomatic haemorrhage.
The reduction in death or dependency may not apply to streptokinase treatment.
While there does seem to be a direct link between blood pressure and risk of recurrent stroke, acute blood pressure
lowering in acute ischaemic stroke may actually lead to increased cerebral ischaemia.
Neuroprotective drugs do not seem to significantly reduce the risk of poor outcome (including death) or to improve
outcome in people with ischaemic stroke.
In young people with malignant middle cerebral artery (MCA) infarction, decompressive hemicraniectomy is an
effective life-saving treatment.
In people with primary supratentorial haematomas, surgical evacuation may be more effective at reducing death
or dependency.
We found no evidence examining the effects of evacuation in people with infratentorial haematoma whose con-
sciousness level is declining.
DEFINITION Stroke is characterised by rapidly developing clinical symptoms and signs of focal, and at times
global, loss of cerebral function lasting over 24 hours or leading to death, with no apparent cause
other than that of vascular origin.
[1]
Ischaemic stroke is stroke caused by vascular insufficiency
(such as cerebrovascular thromboembolism) rather than by haemorrhage.
INCIDENCE/
PREVALENCE
Stroke is the third most common cause of death in most developed countries.
[2]
It is a worldwide
problem; about 4.5 million people die from stroke each year. Stroke can occur at any age, but half
of all strokes occur in people aged over 70 years.
[3]
AETIOLOGY/
RISK FACTORS
About 80% of all acute strokes are ischaemic, usually resulting from thrombotic or embolic occlusion
of a cerebral artery.
[4]
The remainder are caused either by intracerebral or subarachnoid haemor-
rhage.
PROGNOSIS About 10% of people with acute ischaemic strokes will die within 30 days of stroke onset.
[5]
Of
those who survive the acute event, about 50% will still experience some level of disability after 6
months.
[6]
AIMS OF
INTERVENTION
To reduce mortality, impairment, disability, and secondary complications, with minimal adverse
effects of treatment.
OUTCOMES Risk of death or dependency (generally assessed as the proportion of people dead or requiring
physical assistance for transfers, mobility, dressing, feeding, or toileting 3 to 6 months after stroke
onset);
[6]
quality of life, adverse effects.
METHODS Clinical Evidence search June 2009. The following databases were used to identify studies for this
systematic review: Medline 1966 to June 2009, Embase 1980 to June 2009, and The Cochrane
Database of Systematic Reviews 2009, Issue 2 (1966 to date of issue). An additional search within
The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE)
and Health Technology Assessment (HTA). We also searched for retractions of studies included
in the review. Abstracts of the studies retrieved from the initial search were assessed by an infor-
mation specialist. Selected studies were then sent to the contributor for additional assessment,
using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this
review were: published systematic reviews of RCTs and RCTs in any language, at least single
blinded, and containing more than 20 individuals of whom more than 80% were followed up. There
was no minimum length of follow-up required to include studies. We excluded all studies described
as "open", "open label", or not blinded unless blinding was impossible. We included systematic
reviews of RCTs and RCTs where harms of an included intervention were studied applying the
BMJ Publishing Group Ltd 2010. All rights reserved. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Stroke management
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same study design criteria for inclusion as we did for benefits. In addition we use a regular
surveillance protocol to capture harms alerts from organisations such as the US Food and Drug
Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA),
which are added to the reviews as required. To aid readability of the numerical data in our reviews,
we round many percentages to the nearest whole number. Readers should be aware of this when
relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We
have performed a GRADE evaluation of the quality of evidence for interventions included in this
review (see table, p 24 ). The categorisation of the quality of the evidence (into high, moderate,
low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined
populations of interest. These categorisations are not necessarily a reflection of the overall
methodological quality of any individual study, because the Clinical Evidence population and outcome
of choice may represent only a small subset of the total outcomes reported, and population included,
in any individual trial. For further details of how we perform the GRADE evaluation and the scoring
system we use, please see our website (www.clinicalevidence.com).
QUESTION What are the effects of specialised care in people with acute stroke?
OPTION SPECIALISED CARE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Risk of death or dependency
Organised inpatient stroke unit care compared with conventional care Organised inpatient stroke unit care is more
effective at reducing death or dependency at 1 to 5 years compared with conventional (less organised) care but as
yet it is unclear if this effect is sustained at 10 years (moderate-quality evidence).
Integrated care pathways compared with conventional multidisciplinary hospital careWe don't know whether integrated
care pathways are more effective than standard care at 6 months at reducing death or dependency (low-quality evi-
dence).
Early supported discharge (ESD) compared with conventional hospital-based care ESD seems more effective at
reducing death or dependency at median 6 months' follow-up (moderate-quality evidence).
Quality of life
Integrated care pathways compared with conventional multidisciplinary hospital care Integrated care pathways may
result in a lower quality of life at 6 months post-stroke (as measured by EuroQol) compared with standard care, but
we don't know how integrated care pathways compare with standard care at 1 or 3 months (very low-quality evidence)
For GRADE evaluation of interventions for stroke management, see table , p 24 .
Benefits: We found one systematic review comparing organised inpatient stroke unit care versus less-organ-
ised care or conventional care,
[7]
a second systematic review comparing an integrated care pathway
versus conventional multidisciplinary care in hospital,
[8]
and a third systematic review comparing
early supported discharge services versus conventional care.
[9]
Organised inpatient stroke unit care versus conventional care:
The first review (search date 2006) defined stroke care according to level of organisation (from
most organised to least organised: dedicated stroke ward, mixed rehabilitation ward, mobile stroke
team, general medical ward). It found that more-organised care significantly reduced death or de-
pendency at median follow-up of 1 year and at 5 years compared with alternative, less-organised
care, as defined by the reviewers (see table 1, p 20 ).
[7]
Two RCTs identified by the review extended
follow-up to 10 years after stroke.
[10] [11]
The review found that care in a dedicated stroke unit
increased the proportion of people alive and able to live at home; however, there was no significant
difference between groups in death or dependency 10 years after their stroke (see table 1, p 20 ).
The review carried out a subgroup analysis of organised stroke unit care or mobile stroke unit care
compared with general medical ward care. It found that organised stroke unit care significantly re-
duced death or dependency compared with general medical ward care. However there was no
significant difference in death or dependency between mobile inpatient stroke teams and general
medical ward care (see table 1, p 20 ).
Integrated care pathways (ICP) compared with conventional multidisciplinary hospital care:
The second review (search date 2003) analysed one small RCT and found no significant difference
at 6 months in the combined outcome of death or dependency or in death alone (see table 1, p
20 ). However, this analysis, based on a single RCT, may have lacked power to detect clinically
important differences in effect.
[8]
This review found no significant difference between groups in
quality of life (assessed by EuroQol score) at 1 or at 3 months (no further details reported) but
those people who received care using ICP had a significantly lower median EuroQol score at 6
months' follow-up compared with those who received standard care. However, these findings were
BMJ Publishing Group Ltd 2010. All rights reserved. ........................................................... 3
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based on the same single small RCT and should be interpreted with caution (see table 1, p 20 ).
[8]
Early supported discharge (ESD) compared with conventional hospital-based care:
The third systematic review (search date not reported, 12 RCTs, 1659 people) found that ESD
schemes significantly reduced death and dependency after stroke compared with usual care (see
table 1, p 20 ). It found no significant differences in death alone or activities of daily living (ADL)
scores (absolute results not reported, reported as not significant, P value not reported). However,
subgroup analysis according to how the ESD scheme was implemented suggested that an ESD
service was only effective when organised and delivered by a dedicated ESD team (see table 1,
p 20 ).
[9]
Harms: The reviews did not report on adverse effects associated with stroke units.
[7] [8] [9]
Comment: Clinical guide:
Although the proportional reduction in death or dependency seems larger with thrombolysis (see
review on thrombolysis, p 7 ), stroke unit care is applicable to most people with stroke, whereas,
owing to the risk of haemorrhage associated with thrombolysis and the need to begin treatment
within a short time frame (3 hours if possible), it is applicable only to a small proportion of people
with stroke.
The first systematic review did not provide evidence about which aspects of organised inpatient
stroke care led to improved outcome.
[7]
It did perform a number of subgroup analyses comparing
the different types of specialised care. The role of intensive monitoring remains unclear as there
was no significant difference in rates of death or dependency in units with semi-intensive monitoring
compared with those without. No difference was seen in death or dependency between mobile in-
patient stroke teams and general medical ward care, although people cared for by mobile stroke
units faired worse than those cared for on a dedicated stroke unit. However, only one RCT in this
systematic review examined this comparison, and the results should be interpreted with caution.
[12]
Overall duration of stay in the stroke unit was significantly shorter than in a non-stroke unit
setting. However the duration of stay was calculated differently for many of the studies and so
heterogeneity among results limits generalisability.
In an attempt to explain the reasons for improved outcome on dedicated stroke units, a further
analysis of the first systematic review
[7]
compared the numbers of complications and of interventions
to prevent complications recorded in patients cared for on stroke units and in those receiving con-
ventional care.
[13]
An analysis of data from seven RCTs (1652 people), looking at the number of
interventions that occurred to prevent complications, showed an increase in the use of oxygen,
paracetamol, and measures to prevent aspiration on stroke units. Complications following the initial
stroke were gathered from eight RCTs (1824 people) and showed significantly fewer chest infections,
other infections, falls, pressure sores, and stroke extension/recurrence recorded in the stroke units
patients. There was no significant difference seen in the recorded physiological complications (high
or low blood pressure, hyperglycaemia, hypoxia, or pyrexia). The authors suggest that implemen-
tation of measures to prevent complications may partially explain the better outcomes seen. A
separate limited retrospective analysis of one of the RCTs found that several factors (including
early mobilisation, increased use of oxygen, intravenous saline solutions, and antipyretics) might
have been responsible.
[14]
Most RCTs excluded the most mild and most severe strokes. Prospective observational data have
been collected in one large series of over 14,000 people in 80 Swedish hospitals.
[15]
In this series,
people admitted to stroke units had reduced dependence at 3 months (RRR 6%, 95% CI 1% to
11%). Although biases are inherent in such observational data, the findings suggest that the results
of the meta-analysis may be reproducible in routine clinical settings.
QUESTION What are the effects of medical treatment in people with acute ischaemic stroke?
OPTION ASPIRIN. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Early aspirin compared with placebo/no treatment Aspirin taken within 48 hours of stroke onset seems more effective
at reducing death or dependency at 6 months in people with definite or presumed ischaemic stroke, and at increasing
the proportion of people making a complete recovery (moderate-quality evidence).
Aspirin plus heparin compared with aspirin alone Aspirin plus unfractionated or low molecular weight heparin given
within 48 hours of ischaemic stroke onset is no more effective at reducing death or dependency, and is more likely
to increase the risk of symptomatic intracranial haemorrhage or extracranial haemorrhage (moderate-quality evidence).
Stroke management
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Compared with systemic anticoagulation Aspirin and systemic anticoagulants (unfractionated or low molecular weight
heparin) given within 48 hours of ischaemic stroke are equally effective at 3 to 6 months at reducing death or depen-
dency (moderate-quality evidence).
Benefits: Early use of aspirin versus placebo or no treatment:
We found one systematic review (search date 2007, 4 RCTs, 41,291 people with definite or pre-
sumed ischaemic stroke) comparing aspirin started within 14 days of the stroke versus placebo or
no treatment.
[16]
Most (greater than 98%) of the data in the systematic review came from two large
RCTs of aspirin 160 to 300 mg daily started within 48 hours of stroke onset (see comment below).
[17] [18]
One of the RCTs was an unblinded factorial design study comparing aspirin, heparin, aspirin
plus heparin, or no treatment.
[18]
Most people had an ischaemic stroke confirmed by computerised
tomography (CT) scan before randomisation, but people who were conscious could be randomised
before CT scan if the stroke was very likely to be ischaemic on clinical grounds. Treatment duration
varied from 10 to 28 days. The review found that aspirin started within the first 48 hours of acute
ischaemic stroke significantly reduced death or dependency at 6 months' follow-up (9285/20,647
[45%] with aspirin v 9529/20,644 [46%] with placebo/no treatment; RR 0.95, 95% CI 0.91 to 0.99)
and increased the proportion of people making a complete recovery (2 RCTs, 40,541 people: RR
1.06, 95% CI 1.01 to 1.11).
[16]
Aspirin alone versus aspirin plus heparin:
See benefits of systemic anticoagulation, p 5 .
Aspirin versus systemic anticoagulation:
See benefits of systemic anticoagulation, p 5 .
Harms: Early use of aspirin versus placebo or no treatment:
The review found that aspirin caused an excess of about two intracranial and four extracranial
haemorrhages per 1000 people treated, but that these small risks were more than offset by the
reductions in death and disability from other causes.
[16]
Common adverse effects of aspirin (such
as dyspepsia and constipation) were dose related.
[19]
Aspirin alone versus aspirin plus heparin:
See harms of systemic anticoagulation, p 5 .
Aspirin versus systemic anticoagulation:
See harms of systemic anticoagulation, p 5 .
Comment: Early use of aspirin versus placebo:
We found a second meta-analysis
[20]
of the two large RCTs
[17] [18]
included in the systematic
review.
[16]
It also found that aspirin significantly reduced further stroke or death compared with
placebo. It reported that the effect was similar across subgroups (older v younger; male v female;
impaired consciousness or not; atrial fibrillation or not; level of systolic blood pressure; stroke
subtype; timing of CT scanning).
[20]
Clinical guide:
We found no clear evidence on the most effective dose of aspirin in the treatment of acute ischaemic
stroke. One meta-regression analysis of the doseresponse effect of aspirin on stroke found a
uniform effect of aspirin in a range of doses of 501500 mg daily.
[21]
People unable to swallow
safely after a stroke may be given aspirin as a suppository.
In August 2006 the US Food and Drug Administration (FDA) issued a warning that ibuprofen can
interfere with the antiplatelet effects of low-dose aspirin (81 mg/day), potentially rendering aspirin
less effective when used for cardioprotection and stroke prevention.
[22]
Healthcare professionals
should try to avoid prescriptions for long-term concomitant use of ibuprofen and aspirin, and should
advise consumers and patients regarding this interaction.
For further information on long-term use of aspirin see aspirin in review on stroke prevention.
OPTION ANTICOAGULATION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Systemic anticoagulants compared with control (placebo or no treatment) Systemic anticoagulants (unfractionated
heparin, low molecular weight heparin, heparinoids, oral anticoagulants, or specific thrombin inhibitors) may be no
more effective at 3 to 6 months at reducing death or dependency after a stroke (low-quality evidence).
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Systemic anticoagulants compared with aspirin Systemic anticoagulants (unfractionated or low molecular weight
heparin) and aspirin given within 48 hours of ischaemic stroke are equally effective at 3 to 6 months at reducing
death or dependency (moderate-quality evidence).
Aspirin plus heparin compared with aspirin alone Aspirin plus unfractionated or low molecular weight heparin given
within 48 hours of ischaemic stroke onset is no more effective at reducing death or dependency (moderate-quality
evidence).
Note
Systemic anticoagulants are associated with an increased risk of intracranial haemorrhage and extracranial haemor-
rhage.
Benefits: We found three systematic reviews comparing systemic anticoagulants versus usual care, aspirin,
or each other (see table 2, p 22 ),
[23] [24] [25]
and one subsequent RCT
[26]
comparing low
molecular weight heparin (LMWH) versus aspirin (see table 2, p 22 ).
Systemic anticoagulants versus placebo or no treatment:
The first review found no significant difference in death or dependency after 3 to 6 months between
anticoagulants and control (placebo or no treatment; see table 2, p 22 ).
[23]
Systemic anticoagulants versus aspirin:
The second review found no significant difference in death or dependency after 3 to 6 months be-
tween anticoagulants and aspirin.
[24]
The subsequent RCT found no significant difference between
LMWH and aspirin in a combined outcome defined as survival with a Barthel index score 85 or
greater at 6 months (see table 2, p 22 ).
[26]
Unfractionated heparin plus aspirin versus aspirin alone:
The second systematic review found no significant difference in death or dependency between
aspirin plus heparin and aspirin alone (see table 2, p 22 ).
[24]
LMWH or heparinoids versus unfractionated heparin:
The third review provided insufficient evidence to compare anticoagulants versus each other for
death or dependency (see table 2, p 22 ).
[25]
Harms: Systemic anticoagulants versus placebo or no treatment:
The first review found that anticoagulation slightly but significantly increased symptomatic intracranial
haemorrhages and major extracranial haemorrhages within 14 days of starting treatment compared
with control, with an increased risk as dose increased (see table 2, p 22 ).
[23]
Systemic anticoagulants versus aspirin:
The second review found that anticoagulants (unfractionated heparin and LMWH) significantly in-
creased symptomatic intracranial haemorrhage compared with aspirin (see table 2, p 22 ).
[24]
Analysis of this adverse effect by dose found a significantly higher rate of symptomatic intracranial
haemorrhage with high-dose anticoagulants compared with aspirin (see table 2, p 22 ). However,
there was no significant difference between low doses of anticoagulants and aspirin (see table 2,
p 22 ).
[24]
One subsequent RCT found a significantly higher rate of haemorrhagic adverse effects
with LMWH compared with aspirin (see table 2, p 22 ).
[26]
However, there was no significant dif-
ference between groups in reported adverse effects (type and severity not specified) at 6 months'
follow-up (87/180 [48.3%] with LMWH v 83/173 [47.9%] with aspirin; P = 0.95).
Unfractionated heparin plus aspirin versus aspirin alone:
The second systematic review found that unfractionated heparin plus aspirin significantly increased
symptomatic intracranial haemorrhage and major extracranial haemorrhage compared with aspirin
alone (see table 2, p 22 ).
[24]
LMWH or heparinoids versus unfractionated heparin:
In the third review, the number of events was too small to compare the effects of LMWHs or hep-
arinoids with unfractionated heparin on intracranial or extracranial haemorrhage.
[25]
Comment: The reviews found that systemic anticoagulation reduced deep vein thrombosis compared with
control or aspirin, and that low molecular weight heparins or heparinoids were more effective than
unfractionated heparin (see table 2, p 22 ). Results for pulmonary embolism were inconclusive
(see table 2, p 22 ).
[24] [23] [25] [27]
Stroke management
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Alternative treatments to prevent deep venous thrombosis and pulmonary embolism after acute
ischaemic stroke include aspirin and compression stockings. The evidence relating to these will
be reviewed in future Clinical Evidence updates. One large RCT found that high-dose unfractionated
heparin for stroke management resulted in worse outcomes compared with low-dose unfractionated
heparin.
[18]
OPTION THROMBOLYSIS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Any thrombolytic compared with placebo/no thrombolysis Thrombolytics (streptokinase, recombinant tissue plasmino-
gen activators, urokinase, and pro-urokinase) given soon after onset of confirmed ischaemic stroke may be more
effective at reducing death or dependency but may increase mortality at 3 to 6 months (low-quality evidence).
Desmoteplase compared with placebo Desmoteplase given soon after onset of stroke may be no more effective at
achieving a good-clinical-outcome measure (defined as a composite of improvement in National Institutes of Health
Stroke Scale [NIHSS] score of 8 points or greater or an NIHSS score of 1 point or less, a modified Rankin scale
score of 02 points, and a Barthel index of 75100) (low-quality evidence).
Recombinant tissue plasminogen activator compared with placebo/no thrombolysis Recombinant tissue plasminogen
activators given soon after onset of stroke may be more effective at reducing death or dependency (low-quality evi-
dence).
Streptokinase compared with placebo/no thrombolysis Streptokinase given soon after onset of confirmed ischaemic
stroke may be no more effective at reducing death or dependency, but may increase mortality at 3 months (low-
quality evidence).
Note
Thrombolysis has been associated with an increased risk of intracranial haemorrhage
Benefits: We found three systematic reviews
[28] [29] [30]
and two subsequent RCTs.
[31] [32]
Any thrombolytic versus placebo/no thrombolysis:
The first review (search date 2003, 18 RCTs, 5727 highly selected people,
[28]
people with severe
stroke and risk of bleeding excluded) compared intravenous or intra-arterial thrombolysis versus
placebo given soon after the onset of stroke. In the review, all trials used computerised tomography
(CT) or MRI before randomisation to exclude intracranial haemorrhage or other non-stroke disorders.
Results for three different thrombolytic agents (streptokinase, urokinase, and recombinant tissue
plasminogen activator [rtPA]) were included. Two RCTs gave thrombolysis by the intra-arterial
route and the rest used the intravenous route. The review found that any type of thrombolysis sig-
nificantly reduced the composite risk of death or dependency at the end of the trials compared with
no thrombolysis (at end of follow-up at 36 months: 14 RCTs; 4807 people: 1357/2548 [53%] with
thrombolysis v 1310/2259 [58%] with no thrombolysis; OR 0.84, 95% CI 0.75 to 0.95; P = 0.004).
[28]
It found that thrombolysis increased the risk of death by the end of follow-up at 3 to 6 months
compared with no thrombolysis (5675 people; OR 1.33, 95% CI 1.15 to 1.53; P = 0.0002).
[28]
This
excess of deaths was offset by proportionately fewer people being alive but dependent 6 months
after stroke onset. The net effect was a reduction in the proportion of people dead or dependent.
The second review (search date 2003, 11 RCTs, 3709 people) had different inclusion and exclusion
criteria.
[29]
The review identified seven RCTs assessing rtPAs, two RCTs assessing pro-urokinase,
and two RCTs assessing ancrod. It did not include any RCTs on streptokinase. A placebo compar-
ison was used in nine included RCTs and a heparin control in two RCTs. Two RCTs gave throm-
bolysis by the intra-arterial route, and the rest used an intravenous route. Mean follow-up was 5
months (range 112 months). The review found no significant difference between thrombolysis
and control in all-cause mortality at end of follow-up, or in all-cause mortality within 1 month (at the
end of follow-up; 11 RCTs: 367/1904 [19%] with thrombolysis v 325/1805 [18%] with no thrombol-
ysis; OR 1.07, 95% CI 0.8 to 1.39; P = 0.3; within 1 month: 9 RCTs; OR 1.14, 95% CI 0.75 to 1.73;
P = 0.6, absolute numbers not reported).
[29]
Desmoteplase versus placebo/no thrombolysis:
The first subsequent RCT (186 people with acute ischaemic stroke and subjectively identified tissue
at risk on MRI [diffusion/perfusion mismatch] or CT perfusion imaging) compared two doses of
desmoteplase (90 and 125 micrograms/kg) with placebo, given 3 to 9 hours (mean about 400
minutes) after stroke onset. The RCT found no significant difference between groups in response
rate using a composite good-clinical-outcome measure (defined as a composite of improvement
in National Institutes of Health Stroke Scale [NIHSS] score of 8 points or greater or an NIHSS score
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of 1 point or less, a modified Rankin scale score of 02 points, and a Barthel index of 75100) at
day 90 (27/57 [47%] with desmoteplase 90 micrograms/kg v 24/66 [36%] with desmoteplase 125
micrograms/kg v 29/63 [46%] with placebo; P = 0.47 [among groups]).
[31]
Recombinant tissue plasminogen activator (rtPA) versus placebo/no thrombolysis:
The first review also pooled data separately for trials assessing intravenous rtPA.
[28]
It found that
rtPA significantly reduced death or dependency at the end of the studies compared with no
thrombolysis (6 RCTs; 2830 people: 729/1431 [51%] with rtPA v 789/1399 [56%] with no thrombol-
ysis; OR 0.80, 95% CI 0.69 to 0.93; P = 0.003). The second subsequent RCT (821 people with
acute ischaemic stroke) compared the rtPA alteplase (0.9 mg/kg, maximum 90 mg), given intra-
venously between 3 and 4.5 hours after stroke onset, with placebo. It found that alteplase signifi-
cantly increased the proportion of people with a good outcome (defined as a modified Rankin score
of 0 or 1) compared with placebo after 90 days' follow-up (219/418 [52%] with alteplase v 182/403
[45%] with placebo; OR 1.34, 95% CI 1.02 to 1.76; P = 0.04).
[32]
Streptokinase versus placebo/no thrombolysis:
The first review did not pool data separately for trials assessing streptokinase.
[28]
The third review
(search date not reported, 4 RCTs, 1292 people with acute ischaemic stroke) identified the same
streptokinase RCTs as were identified by the first review, but found no significant difference between
streptokinase and placebo in the proportion of people with the combined outcome of death or de-
pendency (defined as Rankin score of 3 or greater) at 3 months (absolute numbers not reported;
RR 0.99, 95% CI 0.92 to 1.06; P = 0.72).
[30]
It found that streptokinase significantly increased
mortality after 3 months compared with placebo (absolute numbers not reported; RR 1.46, 95% CI
1.24 to 1.73; P less than 0.001).
[30]
Harms: Any thrombolytic versus placebo/no thrombolysis:
In the first systematic review, thrombolysis increased fatal intracranial haemorrhage measured in
the first 7 to 10 days (14 RCTs, 4909 people: OR 4.34, 95% CI 3.14 to 5.99; P less than 0.00001).
[28]
The second review did not report separately on cause-specific mortality, including mortality from
intracranial haemorrhage.
[29]
Desmoteplase versus placebo/no thrombolysis:
The first subsequent RCT reported similar rates of serious adverse effects in all groups (20/57
[35%] with desmoteplase 90 micrograms/kg v 24/66 [36%] with desmoteplase 125 micrograms/kg
v 18/63 [29%] with placebo; significance assessment not reported). It found similar rates of
asymptomatic intracranial haemorrhage within 72 hours between groups (20/57 [35%] with
desmoteplase 90 micrograms/kg v 22/66 [33%] with desmoteplase 125 micrograms/kg v 21/63
[33%] with placebo; significance assessment not reported).
Recombinant tissue plasminogen activator (rtPA) versus placebo/no thrombolysis:
The first review also pooled data separately for rtPAs.
[28]
It found that rtPA significantly increased
fatal intracranial haemorrhage at 7 to 10 days compared with no thrombolysis (6 RCTs, 2826
people; OR 3.6, 95% CI 2.28 to 5.68; P less than 0.00001).
[28]
The second subsequent RCT found
a significant increase in any intracranial haemorrhage and symptomatic intracranial haemorrhage
with alteplase compared with placebo (intracranial haemorrhage: 113/418 [27%] with alteplase v
71/403 [18%] with placebo; OR 1.73, 95% CI 1.24 to 2.42; P = 0.001; symptomatic intracranial
haemorrhage [defined according to ECASS II definition; intracerebral haemorrhage accompanying
neurological decline or death]: 22/418 [5%] with alteplase v 9/403 [2%] with placebo; OR 2.43, 95%
CI 1.11 to 5.35; P = 0.02).
[32]
Streptokinase versus placebo/no thrombolysis:
The third review did not report separately on cause-specific mortality, including mortality from in-
tracranial haemorrhage.
[30]
Comment: Limitations of the evidence:
The systematic reviews found to date have employed different approaches to the specific trials in-
cluded in the analysis. The first review looked at data from trials across a range of thrombolytic
agents (i.e., streptokinase, rtPAs, urokinase, and pro-urokinase).
[28]
There was no significant
heterogeneity of treatment effect overall, but, among the eight trials using intravenous rtPA, hetero-
geneity of results was noted for the outcomes of death, and death or dependency at final follow-
up.
[28]
Explanations for heterogeneity with intravenous rtPA may include the combined use of
antithrombotic agents (aspirin or heparin within the first 24 hours of thrombolysis), stroke severity,
the presence of early ischaemic changes on CT scan, and the time from stroke onset to randomi-
sation. Most trials reported outcomes at 3 months; only one trial reported 1-year outcome data.
[33]
Other systematic reviews include data from other trials not included in the first review.
[29]
One
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systematic review (search date 2003) concluded that current RCT evidence regarding the best
dosage, route of administration, and type of thrombolytic, was inadequate.
[34]
Also, most published
RCT data at the moment does not include people aged over 80 years.
Clinical guide: timing of thrombolysis:
One systematic review (6 RCTs, 2775 people) assessed outcomes in people receiving rtPA com-
pared with placebo within 6 hours of stroke onset.
[35]
It confirmed that the major determinant of
benefit is time of administration of the drug from stroke onset that is, the sooner the better.
[35]
The review suggested there may be benefit beyond 3 hours, but that further trials are needed. An
earlier preliminary pooling of three RCTs (1734 people) suggested that rtPA given between 3 and
6 hours may reduce death or dependency in some people compared with placebo.
[36]
In addition,
a systematic review (search date 2003, 18 RCTs, 5727 people) highlighted the lack of reliable ev-
idence for a difference in outcome between people treated within 3 hours and those treated between
3 and 6 hours from stroke onset.
[28]
However, the first subsequent RCT found no benefit of intra-
venous desmoteplase given 3 to 9 hours (average 6.5 hours) after stroke onset, despite identification
of tissue at risk on MRI or perfusion CT imaging.
[31]
The second subsequent RCT did find a ben-
efit (reduction in disability) with intravenous recombinant tissue plasminogen activator given 3 to
4.5 hours after stroke onset.
[32]
Together, these reviews and RCTs suggest an upper time limit
for beneficial administration of thrombolysis in the region of 4.5 hours, or between 3 and 6 hours,
though this may vary between people. Further trials to define upper time limits in individuals are
warranted, as are trials aimed at determining the benefit of thrombolysis within the 3 to 6 hour
window, with direct comparisons across the full range of time scales.
Clinical guide: barriers to delivery of thrombolysis:
In most developed stroke services, the aim is to initiate thrombolysis within the 3-hour time frame
to ensure that as many eligible people as possible receive treatment. Problems over recognition
of stroke in the community, and failure to admit people quickly to stroke centres, mean that most
arrive too late to be considered for thrombolysis, although about one in four people who arrive
within 3 hours of stroke are suitable for treatment. We found two systematic reviews (search dates
2001
[37]
and 2002
[38]
), which analysed barriers to delivery of thrombolysis
[37]
and assessed
methods to improve efficiency of delivery.
[38]
The second review (10 observational studies, 6345
or more people with acute ischaemic stroke) found that interventions that improved delivery of
thrombolysis were: education programmes to raise public awareness of stroke symptoms; training
programmes for paramedics to improve diagnostic skills and hasten rapid triage to hospital; and
reorganisation to streamline patient flows, particularly to brain imaging, once in hospital.
[38]
Clinical guide: assessing individual patient risk:
Evidence of benefit of thrombolysis to people aged over 80 years is limited because of the small
numbers in this age group included in trials to date. There is currently no consensus about giving
thrombolysis after 3 hours in this age group. Newer magnetic resonance imaging techniques, such
as diffusion/perfusion-weighted imaging, may be helpful in patient selection, but studies using these
techniques have so far been small.
[39]
Two systematic reviews, using different study inclusion cri-
teria, found that factors likely to be associated with haemorrhage risk are hyperglycaemia, clinical
stroke severity (NIHSS score), extensive hypoattenuation on pre-treatment CT or diffusion lesion
on MRI, and increasing age.
[40] [41]
OPTION NEUROPROTECTIVE AGENTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Calcium channel blockers compared with placebo Calcium channel blockers are no more effective at reducing the
risk of poor outcome (including death) or reducing mortality (high-quality evidence).
Citicoline compared with placebo Citicoline given within 24 hours of a stroke seems more effective at increasing the
proportion of people completely recovered after 3 months but seems no more effective at reducing mortality in people
with moderate to severe stroke (moderate-quality evidence).
GABA agonists compared with placebo Piracetam is no more effective at reducing dependency or death at 12 weeks
in people with acute ischaemic stroke. Clomethiazole is no more effective at improving neurological recovery or at
improving functional independence at 3 months (high-quality evidence).
Glycine antagonists (gavestinel) compared with placebo Gavestinel is no more effective at reducing death or depen-
dency at 1 to 3 months (moderate-quality evidence).
Lubeluzole compared with placebo Lubeluzole is no more effective at reducing death or dependency at 4 to 12 weeks
(high-quality evidence).
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Magnesium compared with placebo Magnesium is no more effective at reducing death and dependency (moderate-
quality evidence).
N-methyl-D-aspartate receptor antagonists compared with placebo N-methyl-D-aspartate receptor antagonists
(gavestinel, selfotel, and aptiganel) are no more effective at reducing death or dependence (high-quality evidence).
5-hydroxytryptamine-2 serotonergic antagonists (naftidrofuryl) compared with placebo Naftidrofuryl is no more effective
at reducing death, dependence, or disability in people with acute ischaemic or haemorrhagic stroke (high-quality
evidence).
Intercellular adhesion molecule-1 (ICAM-1) antibody (enlimomab) compared with placebo Enlimomab given within
6 hours of acute ischaemic stroke seems no more effective at reducing mortality and seems less effective at reducing
disability (assessed by Modified Rankin scales scores) at 90 days (moderate-quality evidence).
Benefits: Calcium channel blockers versus placebo:
We found two systematic reviews comparing calcium channel blockers versus placebo.
[42] [43]
The first review (search date 1999) found no significant difference between calcium channel
blockers and placebo in risk of poor outcome (including death) or death at the end of follow-up
(poor outcome including death: 22 RCTs, 6877 people: 1765/3825 [46%] with calcium channel
blockers v 1256/3052 [41%] with placebo; RR 1.04, 95% CI 0.98 to 1.09; death: 28 RCTs, 7522
people: 911/4145 [22%] with calcium channel blockers v 699/3377 [21%] with placebo; RR 1.07,
95% CI 0.98 to 1.17).
[42]
The second review (search date 1999)
[43]
included one additional RCT
(454 people)
[44]
that was stopped prematurely because of publication of the results of the first re-
view.
[42]
Inclusion of its data did not change the results of the first review.
Citicoline versus placebo:
We found one systematic review (search date not reported, 4 RCTs, 1652 people with moderate
to severe stroke) comparing citicoline given within 24 hours of stroke onset versus placebo.
[45]
It
found that citicoline significantly increased the proportion of people completely recovered at 3
months compared with placebo (25% with citicoline v 20% with placebo; OR 1.33, 95% CI 1.10 to
1.62; P = 0.0034, absolute numbers not reported). However, it found no significant difference in
mortality between citicoline and placebo (19% with citicoline v 18% with placebo; reported as not
significant; P value and absolute numbers not reported).
GABA agonists versus placebo:
We found one systematic review (search date 2005, 3 RCTs, 1002 people with acute ischaemic
stroke)
[46]
and two additional RCTs.
[47] [48]
The systematic review found no significant difference
in death or dependency at 12 weeks between piracetam (a GABA agonist) and placebo (1 RCT
923 people: 293/460 [64%] with piracetam v 294/464 [63%] with placebo; RR 1.00, 95% CI 0.91
to 1.11).
[46]
The two additional RCTs found similar results.
[47] [48]
The first additional RCT (1360
people with acute stroke) found no significant difference in functional independence between
clomethiazole (a GABA agonist) and placebo (380/680 [56%] with clomethiazole v 370/680 [55%]
with placebo; OR 1.05, 95% CI 0.85 to 1.30).
[47]
The second additional RCT (1198 people with
major acute ischaemic stroke treated within 12 hours) found no significant difference in neurological
recovery at 3 months between clomethiazole and placebo (Barthel index 60 or greater: 42/586
[7%] with clomethiazole v 46/583 [8%] with placebo; OR 0.81, 95% CI 0.62 to 1.05).
[48]
Glycine antagonists (gavestinel) versus placebo:
We found one systematic review (search date 2001, 8 RCTs, 3751 people),
[49]
one additional
RCT,
[50]
and one subsequent RCT
[51]
comparing glycine antagonists (gavestinel) versus placebo.
The review found no significant difference between gavestinel and placebo in death or dependency,
or in mortality after 1 to 3 months (death or dependency: 1023/1949 [52%] with gavestinel v 942/1842
[51%] with placebo; RR 1.02, 95% CI 0.96 to 1.08; mortality: 389/1949 [20%] with gavestinel v
337/1802 [19%] with placebo; RR 1.10, 95% CI 0.96 to 1.25). The additional RCT (1804 conscious
people with limb weakness assessed within 6 hours of stroke onset) found no significant difference
between gavestinel and placebo in survival and outcome at 3 months, as measured using the
Barthel index (ARR +1.0%, 95% CI 3.5% to +6.0%).
[50]
The subsequent RCT (1367 people with
predefined level of limb weakness and functional independence before stroke) also found no sig-
nificant difference in survival and outcome at 3 months, measured using the Barthel index (ARI
+1.9%, 95% CI 3.8% to +6.4%).
[51]
Lubeluzole versus placebo:
We found two systematic reviews (search dates 2001),
[49] [52]
which compared the ion channel
modulator lubeluzole versus placebo. The first review (5 RCTs, 3553 people) found no significant
difference between lubeluzole and placebo in the combined outcome of death/dependence
BMJ Publishing Group Ltd 2010. All rights reserved. .......................................................... 10
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(1080/1842 [59%] with lubeluzole v 993/1711 [58%] with placebo; RR 1.00, 95% CI 0.95 to 1.06).
[49]
The second review (5 RCTs, 3510 people) also found no significant difference between
lubeluzole (5, 10, or 20 mg/day for 5 days) and placebo in death/dependency at 4 to 12 weeks'
follow-up (4 RCTs, 3464 people: 1005/1797 [56%] with lubeluzole v 920/1667 [55%] with placebo;
RR 1.02, 95% CI 0.96 to 1.08).
[52]
Four RCTs were identified by both reviews.
Magnesium versus placebo:
We found one systematic review (search date 2001, 4 RCTs, 162 people)
[49]
and one subsequent
RCT.
[53]
The review found no significant difference in the combined outcome of death or depen-
dency between magnesium and placebo (30/88 [34%] with magnesium v 33/74 [45%] with placebo;
RR 0.84, 95% CI 0.57 to 1.22).
[49]
The subsequent RCT (2589 people with acute ischaemic stroke)
found no significant difference in the combined outcome of death or dependency between magne-
sium (16 mmol IV for 15 minutes followed by 65 mmol over 24 hours) and placebo (OR 0.95, 95%
CI 0.80 to 1.13; absolute numbers not reported).
[53]
N-methyl-D-aspartate (NMDA) receptor antagonists versus placebo:
We found one systematic review (search date 2001, 10 RCTs, 6317 people) comparing NMDA
receptor antagonists (gavestinel, selfotel, and aptiganel) versus placebo.
[49]
It found no significant
difference between NMDA receptor antagonists and placebo in the combined outcome of death or
dependence (1674/3336 [50%] with NMDA receptor antagonists v 1453/2981 [49%] with placebo;
RR 1.02, 95% CI 0.98 to 1.08). We found three additional RCTs (2 publications).
[54] [55]
Two RCTs
(reported in one publication) assessing selfotel found no significant difference in the proportion of
people with a Barthel index greater than 60, but data were limited as the trials were terminated
because of adverse outcomes after only 31% of the total planned patient enrolment, and a non-
significant trend towards increased mortality (mortality day 30: 54/280 [19%] with selfotel v 37/286
[13%] with placebo; P = 0.05).
[54]
Similarly, one RCT comparing aptiganel versus placebo was
terminated early because of lack of efficacy and a non-significant trend towards increased mortality
(26% with aptiganel v 19% with placebo; P = 0.06; absolute numbers not reported).
[55]
5-hydroxytryptamine-2 serotonergic antagonists (naftidrofuryl) versus placebo:
We found one systematic review (search date 2006, 6 RCTs, 1274 people with acute ischaemic
or haemorrhagic stroke) comparing naftidrofuryl versus placebo.
[56]
The review found no significant
difference at end of follow-up between naftidrofuryl and placebo in mortality, or in combined death
or dependency/disability (mortality: 6 RCTs, 1274 people; 130/638 [20.4%] with naftidrofuryl v
126/636 [19.8%] with placebo; RR 1.02, 95% CI 0.82 to 1.27; combined death or dependency/dis-
ability: 3 RCTs, 750 people; 231/381 [61%] with naftidrofuryl v 230/369 [62%] with placebo; RR
0.98, 95% CI 0.87 to 1.10).
[56]
Intercellular adhesion molecule-1 (ICAM-1) antibody (enlimomab) versus placebo:
We found one RCT (625 people within 6 hours of acute ischaemic stroke) comparing enlimomab
given by intravenous infusion versus placebo.
[57]
The primary outcome was disability at 90 days.
The RCT found that enlimomab was associated with significantly worse overall Modified Rankin
Scale scores at 90 days compared with placebo (Modified Rankin Grade: P = 0.004; absolute
numbers not reported). The RCT found no significant difference between groups in mortality at 90
days, although mortality was higher in the enlimomab group (70/317 [22%] with enlimomab v 50/308
[16%] with placebo; P = 0.051).
[57]
Harms: Calcium channel blockers versus placebo:
The systematic review found no significant difference in overall adverse effects between calcium
channel blockers and placebo (OR 1.19, 95% CI 0.97 to 1.47), although one RCT identified by the
review found that flunarizine significantly increased adverse effects, particularly superficial throm-
bophlebitis, compared with placebo (OR 3.73, 95% CI 2.21 to 6.29; see comment below).
[42]
Indirect
and limited comparisons of intravenous versus oral administration in the review found no significant
difference in adverse events (ARI intravenous v oral: +2.3%, 95% CI 0.9% to +3.7%; RRI +17%,
95% CI 3% to +41%).
Citicoline versus placebo:
The review found comparable rates of overall adverse effects between citicoline and placebo, al-
though citicoline significantly increased leg oedema, falls, anxiety, depression, and urinary inconti-
nence (P less than 0.05 for all outcomes).
[45]
GABA agonists versus placebo:
The review gave no information on adverse effects.
[46]
The second additional RCT (1198 people)
found that clomethiazole significantly increased somnolence and rhinitis compared with placebo
(somnolence: 51% with clomethiazole v 13% with placebo; rhinitis: 6% with clomethiazole v 2%
with placebo; P values not reported).
[48]
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Glycine antagonists (gavestinel) versus placebo:
[49]
Lubeluzole versus placebo:
The first review gave no information on adverse effects.
[49]
The second review found that, at any
dose, lubeluzole was associated with a significant increase in the risk of having a heart conduction
disorder (Q-T prolongation to more than 450 milliseconds on ECG) at the end of follow-up (4 RCTs,
3269 people: 196/1659 [12%] with lubeluzole v 156/1610 [10%] with placebo; RR 1.23, 95% CI
1.05 to 1.45).
[52]
There was no significant difference in incidence of heart rhythm disorders (atrial
fibrillation, ventricular tachycardia or fibrillation, torsade de pointes) at the end of the scheduled
follow-up (5 RCTs, 3501 people: 126/1822 [7%] with lubeluzole v 91/1679 [5%] with placebo; RR
1.26, 95% CI 0.97 to 1.64).
[52]
Magnesium versus placebo:
[49]
The RCT found similar low rates of hypoten-
sion, cardiac failure, cardiac conduction block, and flushing between magnesium versus placebo
(statistical analysis not reported for any outcome).
[53]
N-methyl-D-aspartate (NMDA) receptor antagonists versus placebo:
[49]
The two RCTs (reported in one publication)
of selfotel
[54]
and the RCT of aptiganel
[55]
gave no information on adverse effects of treatment.
5-hydroxytryptamine-2 serotonergic antagonists (naftidrofuryl) versus placebo:
The review of naftidrofuryl (3 RCTs, 492 people) found no significant difference between naftidrofuryl
and placebo in minor adverse effects, although the incidence of adverse effects was higher with
naftidrofuryl (23/243 [9%] with naftidrofuryl v 12/249 [5%] with placebo; RR 1.86, 95% CI 0.95 to
3.64).
[56]
No trials reported the effects of naftidrofuryl on the risk of early death or deterioration or
quality of life. The review found no significant difference between naftidrofuryl and placebo in the
risk of serious adverse effects (9/216 [4%] with naftidrofuryl v 6/226 [3%] with placebo; OR 1.46,
95% CI 0.55 to 3.93).
[56]
Intercellular adhesion molecule-1 (ICAM-1) antibody (enlimomab) versus placebo:
The RCT found higher rates of adverse effects with enlimomab compared with placebo (44% with
enlimomab v 30% with placebo; absolute numbers not reported, statistical significance not assessed).
The most common adverse effects reported were fever and infection.
[57]
Comment: Calcium channel blockers:
Flunarizine is an antihistamine with calcium channel-blocking activity. Calcium channel blockers
have antihypertensive action.
Applying the evidence; timing of neuroprotective agents:
We found one systematic review (search date 2001, 6 phase III trials, 5345 people with acute is-
chaemic stroke), which assessed how long from stroke onset neuroprotective drug treatment was
initiated.
[58]
It found that only 6% of trial participants received neuroprotective agents within 3
hours of stroke onset.
Other neuroprotective agents:
We found one systematic review and two RCTs examining the effects of other neuroprotective
agents (tirilazad [a steroid derivative], NXY 059 [a free radical-trapping agent] and DP-b99), which
are not currently licensed or available for use at the time of writing this Clinical Evidence review.
We have briefly described these studies here, and will re-assess these for inclusion if they become
available at the time of the next update.
One systematic review (search date 2001, 6 RCTs, 1757 people with acute ischaemic stroke) found
that tirilazad significantly increased death and disability at 3 months' follow-up compared with
placebo (358/858 [42%] with tirilazad v 300/793 [38%] with placebo; OR 1.23, CI 1.01 to 1.51).
[59]
It found that tirilazad significantly increased the risk of injection-site phlebitis compared with
placebo (6 RCTs: 195/820 [24%] with tirilazad v 79/750 [11%] with placebo; RR 2.31, 95% CI 1.83
to 2.92).
[59]
One RCT published in two publications (1699 people within 6 hours of acute ischaemic
stroke) found that NXY 059 significantly improved disability assessed by the modified Rankin scale
compared with placebo after 7, 30, and 90 days (90 days: OR 1.20, 95% CI 1.01 to 1.42; P = 0.038,
absolute results displayed graphically). It found significantly improved disability scores assessed
by National Institutes of Health Stroke Scale (NIHSS) and by Barthel index at day 7 and day 30,
but no significant difference between groups at 90 days (NIHSS: day 7, day 30: P = 0.003, day 90:
P = 0.86; Barthel index: day 7, day 30: P less than 0.0001, day 90: P = 0.14, absolute results dis-
played graphically). It found no significant difference between groups in mortality after 90 days
(17% with NXY 059 v 16.6% with placebo; P = 0.89).
[60] [61]
One RCT (150 people with stroke,
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signs of cortical involvement, NIHSS score 720) found no significant difference between DP-b99
(given within 19 hours of stroke onset) versus placebo for 4 days in disability or mortality after 90
days (disability; median change in NIHSS score from baseline: 6.0 with DP-b99 v 5.0 with
placebo; P = 0.56; mortality: 12/75 [16%] with DP-b99 v 15/75 [20%] with placebo; P = 0.56).
[62]
It found no significant difference between groups in serious adverse effects (including brain oede-
ma/herniation, cerebral haemorrhage, pneumonia, anaemia, cardiac arrest, multiple organ failure,
recurrent stroke, convulsions, and septic shock) (35/75 [47%] with DP-b99 v 28/75 [37%] with
placebo; P = 0.32).
[62]
OPTION BLOOD PRESSURE REDUCTION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Compared with placebo Antihypertensive drugs may be no more effective at decreasing death or dependency in
people with ischaemic stroke (moderate-quality evidence).
Benefits: We found one systematic review,
[63]
two additional RCTs,
[64] [65]
and one subsequent RCT.
[66]
The review (search date 2007, 12 RCTs, 1153 people with acute ischaemic or haemorrhagic stroke)
compared interventions aimed at altering blood pressure in people with acute stroke versus
placebo (see comment below).
[63]
A total of 11 RCTs investigated interventions aimed at lowering
blood pressure and included: nimodipine or nicardipine (3 RCTs, 75 people); captopril, perindopril,
or lisinopril (3 RCTs, 35 people); candesartan (1 RCT, 173 people); clonidine (1 RCT, 2 people);
bendrofluazide (1 RCT, 18 people); glyceryl trinitrate (3 RCTs, 88 people); and unclassified or
combined antihypertensives (1 RCT, 203 people). One RCT (9 people) investigated the effect of
phenylephrine to raise blood pressure in people with stroke. The review found no significant differ-
ence between treatment aimed at lowering blood pressure in acute stroke and placebo in death or
dependency at follow-up (14 days to 3 months in 5 RCTs, not given in 2 RCTs) (7 RCTs, 586
people: 152/309 [49%] with interventions aimed at lowering blood pressure v 129/277 [47%] with
placebo; OR 1.05, 95% CI 0.76 to 1.47). It found no significant difference between groups in case
fatality within 1 month (proportion of people who died owing to stroke: 11/166 [7%] with interventions
aimed at lowering blood pressure v 14/195 [7%] with placebo; RR 0.92, 955 CI 0.39 to 2.16). The
authors concluded that there is insufficient evidence to evaluate the effect of altering blood pressure
on outcome during acute phase of stroke.
[63]
The first additional RCT (295 people with acute ischaemic stroke) compared nimodipine (a calcium
channel blocker) versus placebo (see comment below).
[64]
The RCT was stopped prematurely
because of an excess in unfavourable neurological outcomes in the nimodipine-treated group.
Exploratory analyses confirmed that this negative correlation was related to reductions in mean
arterial blood pressure and diastolic blood pressure (arterial blood pressure: P = 0.02; diastolic
blood pressure; P = 0.0005; absolute numbers not reported).
The second additional RCT (302 people with acute ischaemic stroke) assessed beta-blockers
(atenolol or propranolol).
[65]
The RCT found no significant difference between beta-blockers and
placebo at 6 months in mortality or in the proportion of people achieving a good outcome (defined
as living at home) (mortality: 34/101 [34%] with atenolol v 33/101 [33%] with propranolol v 23/100
[23%] with placebo; reported as not significant; good outcome: 56/101 [55%] with atenolol v 58/101
[57%] with propranolol v 64/100 [64%] with placebo; reported as not significant).
The subsequent RCT (179 people with acute stroke, and systolic blood pressure above 160 mgHg)
assessed labetalol, lisinopril, or placebo given for 2 weeks. It found no significant difference in the
primary outcome (death or dependency, with dependency defined as an modified Rankin scale
score greater than 3) between active treatment (labetalol or lisinopril) and placebo at 2 weeks
(69/113 [61%] with active treatment v 35/59 [59%] with placebo; RR 1.03, 95% CI 0.80 to 1.33;
P = 0.82).
[66]
The authors commented that the study may have been underpowered to detect
smaller but clinically significant changes between groups in this primary outcome. It found no sig-
nificant difference between active treatment (labetalol or lisinopril) or placebo in early neurological
deterioration (defined as increase in National Institutes of Health Stroke Scale [NIHSS] score of 4
points or greater at 72 hours) (7/113 [6%] with active treatment v 3/59 [5%] with placebo; RR 1.22,
95% CI 0.32 to 4.54; P = 0.76). The RCT found that mortality was lower with active treatment
compared with placebo at 3 months, but this was of borderline significance (11/113 [10%] with
active treatment v 12/59 [20%] with placebo; HR 0.40, 95% CI 0.2 to 1.0; P = 0.05).
Harms: The review did not report on adverse effects of treatments.
[63]
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The first additional RCT suggested that people treated with antihypertensive drugs may have a
worse clinical outcome (see benefits section).
[64]
The second additional RCT found similar rates
of withdrawal due to suspected adverse effects (details not reported) between atenolol or propranolol
and placebo (9 with atenolol v 5 with propranolol v 5 with placebo, statistical analysis not reported).
It found that a total of 8 people were withdrawn from the study owing to definite adverse effects
(details not reported) with atenolol or propranolol compared with none with placebo (statistical
analysis not reported).
[65]
The subsequent RCT found no significant difference between active treatment (labetalol or lisinopril)
and placebo in serious adverse effects (details not given) (28 with labetalol v 33 with lisinopril v 35
with placebo; RR 0.91 [active treatment v placebo], 95% CI 0.69 to 1.12; P = 0.50).
[66]
Comment: The RCTs identified by the first review collected insufficient clinical data for an analysis of the relation
between changes in blood pressure and clinical outcome.
[63]
The authors of the systematic review only included RCTs with the specific aim of altering blood
pressure, as they felt that there were methodological differences between studies that aimed to
alter blood pressure and those that may, or may not, have measured blood pressure as part of
their protocol.
[63]
Although treatment with the calcium channel blocker nimodipine was intended
for neuroprotection, blood pressure was lower in the treatment group in the trial.
[64]
Calcium
channel blockers are both antihypertensive agents and neuroprotective agents. They are considered
specifically in the neuroprotective agents, p 9 option.
QUESTION What are the effects of decompressive hemicraniectomy in acute ischaemic stroke?
OPTION DECOMPRESSIVE HEMICRANIECTOMY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . New
Compared with optimum medical care Decompressive hemicraniectomy may be more effective at reducing mortality
at 30 days to 1 year. We don't know whether it is more effective at reducing disability (low quality-evidence).
Quality of life
Compared with optimum medical care We don't know whether decompressive hemicraniectomy is more effective at
improving quality-of-life scores (assessed by SF-36) at 1 year (low quality-evidence).
Benefits: We found three RCTs comparing decompressive hemicraniectomy versus optimum medical care.
[67] [68] [69]
The first RCT (38 people aged up to 55 years with a malignant middle cerebral artery [MCA] infarction
as per the following criteria: National Institutes of Health Stroke Scale [NIHSS] 16 or greater including
a score 1 or greater for item 1a [level of consciousness]; ischaemic signs involving over 50% for
the MCA territory on computed tomography [CT]; and a diffusion-weighted imaging (DWI) infarct
volume greater than 145 cm
3
) compared decompressive craniectomy plus standard medical
treatment performed within 30 hours (mean 21 hours) after the onset of symptoms versus standard
medical treatment alone.
[67]
A total of 11/20 (55%) people having decompressive craniectomy also
had duraplasty. The trial was stopped prematurely because of slow recruitment, a high difference
in mortality between the two groups, and to organise a pooled analysis of the data from this trial
and the two other similar European trials (see comment). From the available data, the RCT found
that decompressive craniectomy plus standard medical treatment significantly reduced mortality
compared with standard medical treatment alone at 6 months' follow-up (5/20 [25%] with decom-
pressive craniectomy plus standard medical treatment v 14/18 [78%] with standard medical treatment
alone; P less than 0.001). It found no significant difference between groups in the primary outcome
of moderate disability or better at 6 months; however, this was higher with decompressive
craniectomy plus standard medical treatment (proportion of people with modified Rankin scale
[mRS] score 3 or less: 5/20 [25%] with decompressive craniectomy plus standard medical treatment
v 1/18 [6%] with standard medical treatment alone; P = 0.18).
[67]
The second RCT (32 people aged up to 60 years with malignant MCA infarction as per the following
criteria: NIHSS greater than 18 for non-dominant and greater than 20 for dominant hemisphere
including a score 1 or greater for item 1a; CT involvement of at least two thirds of the MCA territory
and including at least part of the basal ganglia) compared decompressive surgery plus conservative
treatment within 36 hours after the onset of symptoms versus conservative treatment alone.
[68]
The study applied a sequential design. The first end point of the RCT was mortality after 30 days
and the primary outcome was the mRS at 6 months, which was dichotomised between good (03)
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and poor (46). However, recruitment in the study was terminated after it found a significant differ-
ence between treatments in mortality at 30 days. The RCT was subsequently terminated early
based on a calculation which suggested it was underpowered to show a 20% difference for the
primary outcome measure, and also in light of the results of the pooled analysis of the three RCTs
(see comment). The RCT found that hemicraniectomy plus conservative treatment significantly
improved survival compared with conservative treatment alone at 30 days (15/17 [88%] with hem-
icraniectomy plus conservative treatment v 7/15 [47%] with conservative treatment alone; P = 0.02).
[68]
The third RCT (64 people aged up to 60 years with space-occupying hemispheric infarction as per
the following criteria: NIHSS 16 or greater for right-sided and 21 or greater for left-sided lesions;
decrease in consciousness; involvement of at least two thirds of MCA territory with space-occupying
oedema on CT) compared surgical decompression within 99 hours after the onset of symptoms
versus best medical treatment.
[69]
The primary outcome measure was the mRS at 1 year, which
was dichotomised between good (03) and poor (46). The RCT found no significant difference
between groups with respect to the primary outcome (proportion of people with a poor outcome:
24/32 [75%] with surgical v 24/32 [75%] with best medical treatment; ARR 0%, 95% CI 21% to
+21%; P = 1.00). However, recruitment in the study was stopped early after it was decided that it
was highly likely to be underpowered to find a statistically significant difference between groups in
the primary outcome with the planned sample size (112 people). The RCT found that surgical
treatment significantly reduced mortality compared with the best medical treatment at 1 year (7/32
[22%] with surgical v 19/32 [59%] with best medical treatment; ARR 38%, 95% CI 15% to 60%;
P = 0.002).
[69]
It found that surgery significantly decreased the physical summary score on the
SF-36 (quality of life) scale (scale not defined, higher scores indicate a more favourable outcome)
compared with best medical care (average score: 29 with surgery v 36 with best medical care;
mean difference 8, 95% CI 14 to 1; P = 0.02). It found no significant differences between the
two treatment groups in the mental summary score of the SF-36 score, mood, or proportion of
people (patient or carer) dissatisfied with treatment (all reported as not significant).
[69]
Harms: The first RCT reported serious and other major adverse effects (including death from brain hernia-
tion/other causes, inhalation pneumonia, venous thromboembolic complications, seizures, depres-
sion, urinary tract infection, cerebral abscess, jejunostomy, tracheostomy, neuroalgodystrophy,
and gastric ulcer); no statistics were provided but the numbers were small.
[67]
The second RCT gave no information on adverse effects of treatments.
[68]
The third RCT listed adverse effects (including symptomatic epidural haematoma [1 person], CSF
leak [2 people], and epileptic seizures [1 person], with surgery) but did not report a statistical
comparison between groups.
[69]
Comment: Pooled analysis of the above three RCTs was done in order to obtain sufficient data that provide
a reliable estimate of the effects of decompressive surgery in malignant MCA infarction.
[70]
For
the purpose of this analysis, only people (93 people aged up to 60 years [51 had surgery and 42
had conservative treatment]) who had treatment up to 48 hours of symptoms onset were included.
The primary outcome measure was the score on mRS at 1 year dichotomised between favourable
(mRS 04) and unfavourable (mRS 5 and death) and was significantly in favour of decompressive
surgery (favourable outcome: 75% with decompressive surgery v 24% with conservative treatment;
ARR 51%, 95% CI 34% to 69%; P less than 0.0001). It found that mortality at 1 year was signifi-
cantly lower in the surgical group (ARR 50%, 95% CI 33% to 67%; P less than 0.0001).
[70]
QUESTION What are the effects of surgical evacuation for intracerebral haematomas?
OPTION EVACUATION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Surgery compared with medical treatment Surgery plus medical treatment seems more effective than medical
treatment alone at reducing death or dependency in people with primary supratentorial intracerebral haemorrhage,
but we don't know whether craniotomy is more effective (moderate-quality evidence).
Benefits: In people with supratentorial haematomas:
We found one systematic review (search date 2007, 10 RCTs, 2059 people with CT confirmed
primary supratentorial intracranical haematoma)
[71]
and one additional RCT.
[72]
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The review compared surgery plus medical versus medical treatment. The primary outcome was
death or dependency. It found that surgery plus conservative care significantly reduced death or
dependency (defined as assistance from other people for their activities of daily living after 36
months) compared with conservative care alone (9 RCTs, 1994 people: 628/996 [63%] with surgery
plus conservative care v 705/998 [71%] with conservative care alone; OR 0.71, 95% CI 0.58 to
0.88; P = 0.001) and death at final follow-up (36 months) (10 RCTs, 2059 people: 278/1030 [17%]
with surgery plus conservative care v 346/1029 [34%] with conservative care alone; OR 0.74, 95%
CI 0.61 to 0.90; P = 0.003). Surgery plus medical versus medical treatment was also assessed
according to type of surgery. It found that stereotactic or endoscopic surgery significantly reduced
death or dependency compared with conservative care (4 RCTs, 566 people: 172/276 [62%] with
stereotactic or endoscopic surgery plus conservative care v 206/290 [71%] with conservative care
alone; OR 0.66, 95% CI 0.46 to 0.96), but there was no significant difference between craniotomy
plus conservative care and conservative care alone (4 RCTs, 769 people: 281/375 [75%] with
craniotomy plus conservative care v 309/394 [78%] with conservative care alone; OR 0.82, 95%
CI 0.59 to 1.15).
[71]
The additional RCT (108 people with subcortical or putaminal spontaneous intracranial haemorrhage
greater than 30 mL on computed tomography) compared craniotomy plus haematoma extraction
(microsurgical approach) versus non-operative management initiated within 8 hours after the stroke.
[72]
The RCT found that craniotomy with early haematoma evacuation significantly improved func-
tional outcome at 1 year (assessed using GOS) compared with non-surgical management (GOS
greater than 3: 33% with surgery v 9% with non-surgical management; P = 0.002; absolute numbers
not reported).
[72]
However, the RCT found no significant difference between groups in mortality
at 1 year (26/54 [48%] with surgical management v 31/54 [57%] with non-operative management;
P = 0.337).
In people with infratentorial haematomas:
We found no systematic review or RCTs assessing the role of surgical evacuation or ventricular
shunting in this population. An RCT is unlikely to be conducted (see comment below).
[73]
Harms: In people with supratentorial haematomas:
The review and additional RCT gave no information on adverse effects.
[71] [72]
In people with infratentorial haematomas:
We found no RCTs.
Comment: Current practice is based on the consensus that people with infratentorial (cerebellar) haematomas
whose consciousness level is declining probably benefit from evacuation of the haematoma. For
people with supratentorial haematomas further trials are needed to identify which patients benefit
from surgery.
GLOSSARY
Barthel index Assessment of functional ability to perform activities of daily living, using 14 different items and a
scale of 020; a higher score denotes greater functional independence.
European Quality of Life5 Dimensions (EuroQol EQ5D) scores range from 0.594 to + 1.000, with lower nu-
merical scores reflecting a poorer quality of life and negative scores associated with a quality of life that is considered
to be worse than death.
Integrated care pathway A model of care that includes definition of therapeutic goals and specification of a timed
plan designed to promote multidisciplinary care, improve discharge planning, and reduce the duration of hospital
stay.
High-quality evidence Further research is very unlikely to change our confidence in the estimate of effect.
Low-quality evidence Further research is very likely to have an important impact on our confidence in the estimate
of effect and is likely to change the estimate.
Moderate-quality evidence Further research is likely to have an important impact on our confidence in the estimate
of effect and may change the estimate.
Very low-quality evidence Any estimate of effect is very uncertain.
SUBSTANTIVE CHANGES
Decompressive hemicraniectomy New option added, for which we found three RCTs, all of which were terminated
early.
[67] [68] [69]
The first RCT found lower mortality with decompressive craniectomy plus standard medical
treatment compared with standard medical treatment but found no significant difference between groups in the pri-
mary outcome of moderate disability or better at 6 months.
[67]
The second RCT found higher survival at 30 days
with hemicraniectomy plus conservative treatment compared with conservative treatment alone .
[68]
The third RCT
found lower mortality in the surgical group compared with the best medical group at 1 year but it found no significant
difference between groups in the proportion of people with a poor outcome (modified Rankin scale score of 46) at
1 year.
[69]
Categorised as Likely to be beneficial.
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Aspirin One systematic review updated.
[16]
It now includes one more small RCT, but the conclusion is unchanged.
Categorisation unchanged (Beneficial).
Specialised care One systematic review updated.
[7]
It now includes eight additional RCTs, and compares different
levels of organised care, but the overall conclusion is unchanged. Another systematic review
[9]
added, which found
a lower rate of death and dependency after stroke in people receiving early supported discharge schemes compared
with usual care. Categorisation unchanged (Beneficial).
Systemic anticoagulation One systematic review
[23]
updated, now includes two additional RCTs, conclusion un-
changed. Another systematic review
[25]
updated, now includes an additional three RCTs, conclusion unchanged.
Categorisation unchanged (Trade-off between benefits and harms).
ThrombolysisTwo RCTs added.
[31] [32]
One RCT found no significant difference between intravenous desmoteplase
(given 3 to 9 hours after stroke onset) and placebo in the proportion of people with a composite good-clinical-outcome
measure at 90 days.
[31]
The second RCT found that recombinant tissue plasminogen activator (alteplase, given in-
travenously within 3 to 4.5 hours after stroke onset) increased the proportion of people with good outcomes at 90
days versus placebo.
[32]
Categorisation unchanged (Trade-off between benefits and harms).
Blood pressure reduction One systematic review
[63]
updated, it now includes one subsequent RCT previously
reported separately in this Clinical Evidence review. The review found no significant difference between treatment
aimed at lowering blood pressure in acute stroke versus placebo, in death or dependency at final follow-up or in case
fatality within 1 month.
[63]
One subsequent RCT added, which found no significant difference in death or dependency
between treatment with labetalol or lisinopril versus placebo after 2 weeks.
[66]
Categorisation changed from Likely
to be ineffective or harmful to Unlikely to be beneficial.
Evacuation One systematic review updated.
[71]
It now includes one RCT previously reported separately in this
Clinical Evidence review and it also supersedes two previously reported systematic reviews as it found similar studies.
The conclusion of this systematic review regarding death or dependency have changed in the positive direction
compared with earlier versions.
[71]
It found that surgery plus conservative care reduced death or dependency
compared with conservative care alone in people with supratentorial intracerebral haemorrhage. However, it gave
no information on harms of evacuation. This change was enough to upgrade the categorisation in this Clinical Evidence
review to trade-off between benefits and harms, but was not enough to qualify for the likely to be beneficial category.
Categorisation changed from Unlikely to be beneficial to Trade-off between benefits and harms.
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intracerebral haemorrhage. In: The Cochrane Library, Issue 2, 2009. Chichester,
UK: John Wiley & Sons, Ltd. Search date 2007
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Science, 1996:430437.
Elizabeth Warburton
Consultant in Stroke Medicine
Neuroscience's Addenbrookes Hospital
Cambridge
UK
Josef A Alawneh
Clinical Neurosciences
University of Cambridge
Cambridge
UK
Philip L Clatworthy
Department of Clinical Neurosciences
Cambridge
UK
Rhiannon S Morris
Department of Clinical Neurosciences
Cambridge
UK
Stroke management
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Competing interests: EW has been reimbursed by Servier, Pfizer, and Boehringer Ingelheim for attending meetings and organising educational events. One research nurse is
funded by Boehringer Ingelheim. JA, PC, and RM declare that they have not competing interests.
We would like to acknowledge the previous contributors of this review, including Gord Gubitz and Peter Sandercock.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a
judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and
harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices.
Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research
we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the
categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately
it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest
extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any
person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, inci-
dental or consequential, resulting from the application of the information in this publication.
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TABLE 1 RCTs of specialised care versus usual care.
Comments Results Comparison Participants Methods Ref
The specialised stroke rehabilitation
unit consisted of a designated area or
Death or dependency at median follow-up of 1 year: OR 0.79, 95%
CI 0.71 to 0.88; P less than 0.0001, absolute numbers for this analysis
not reported
Death or institutional care at median follow-up of 1 year: OR 0.81,
95% CI 0.74 to 0.90; P less than 0.0001, absolute numbers for this
analysis not reported
Death or dependency at 5 years: 2 RCTs; 223/286 (78%) with organ-
ised stroke unit care v 214/249 (86%) with alternative care; OR 0.59,
95% CI 0.38 to 0.92
Death or institutional care at 5 years: 2 RCTs, 172/286 (60%) with
organised stroke unit care v 178/249 (71%) with alternative care; OR
0.62, 95% CI 0.43 to 0.89
Death or dependency at 10 years: 2 RCTs, 249/286 (87%) with organ-
ised stroke unit care v 224/249 (90%) with alternative care; OR 0.77,
95% CI 0.45 to 1.31
Death or institutional care, 10 years after stroke: 2 RCTs, 220/286
(77%) with organised stroke unit care v 214/249 (86%) with alternative
care; OR 0.57, 95% CI 0.37 to 0.88
Stroke unit care v alternative,
less-organised care
6936 people with stroke,
primarily acute ischaemic
stroke
Systematic review,
search date 2006, 31
RCTs
[7]
ward, although some trials used a mo-
bile "stroke team"
Death or dependency at median follow-up of 1 year: 878/1656 (53%)
with stroke unit care v 920/1629 (56%) with general medical ward; OR
0.83, 95% CI 0.72 to 0.96
Stroke unit care v general medi-
cal ward
3285 people with stroke,
primarily acute ischaemic
stroke
Subgroup analysis, 13
RCTs
Death or dependency at median follow-up of 1 year: 233/340 (69%)
with mobile stroke team v 250/359 (70%) with general medical ward;
OR 0.96, 95% CI 0.69 to 1.34
Mobile stroke team v general
medical ward
699 people with stroke, pri-
marily acute ischaemic
stroke
RCTs
This analysis, based on a single RCT,
may have lacked power to detect clini-
cally important differences in effect
Death or dependency at 6 months: 55/76 (72%) with care pathways
v 50/76 (65%) with standard care; OR 1.36, 95% CI 0.68 to 2.72
Death alone at 6 months: 10/76 (13%) with care pathways v 6/76 (8%)
with standard care; OR 1.77, 95% CI 0.61 to 5.14
Quality of life at 6 months: median EuroQol score at 6 months: 63
with care pathways v 72 with standard care; P less than 0.005
Care based on in-hospital care
pathways v standard care
152 people with all types of
stroke
Systematic review,
search date 2003, 1
RCT
[8]
An ESD intervention was defined by the
review authors as "one that aims to ac-
Death or dependency at end of scheduled follow-up (median 6
months): 12 RCTs 375/835 (45%) with ESD v 413/824 (50%) with
conventional care; OR 0.81, 95% CI 0.67 to 0.99; P = 0.04
EDS services v conventional care 1659 people with stroke
admitted to hospital
Systematic review,
search date not report-
ed, 12 RCTs
[9]
celerate discharge from hospital with
the provision of rehabilitation and sup-
port in the community setting". The in-
terventions included (7 RCTs): single
multidisciplinary ESD team co-ordinated
hospital discharge and provided rehabil-
itation at home (3 RCTs): ESD team
co-ordinated discharge and provided
immediate post-discharge care, but not
ongoing rehabilitation (2 RCTs): unco-
ordinated community services or input
from healthcare volunteers
BMJ Publishing Group Ltd 2010. All rights reserved. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
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Comments Results Comparison Participants Methods Ref
months): 7 RCTs; 200/426 (47%) with ESD v 228/416 (55%) with con-
ventional care; OR 0.71, 95% CI 0.54 to 0.94
ESD team co-ordinated hospital
discharge and provided rehabili-
tation at home v conventional
care
842 people with stroke ad-
mitted to hospital
RCTs
months): 3 RCTs; 99/233 (42%) with ESD v 113/231 (49%) with con-
ventional care; OR 0.77, 95% CI 0.54 to 1.11
ESD team co-ordinated dis-
charge and provided immediate
post-discharge care, but not on-
going rehabilitation services v
conventional care
mitted to hospital
RCTs
months): 2 RCTs; 79/176 (45%) with ESD v 72/177 (41%) with conven-
tional care; OR 1.23, 95% CI 0.79 to 1.91
Unco-ordinated community ser-
vices or input from healthcare
volunteer v conventional care
mitted to hospital
RCTs
Ref, reference; ESD, early supported discharge
BMJ Publishing Group Ltd 2010. All rights reserved. ............................................................................................................ 21
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TABLE 2 RCTs of systemic anticoagulation.
Major extracranial haemor-
rhage
Symptomatic intracranial
haemorrhage
DVT and pulmonary embolism Death or dependency Comparison Participants Methods Ref
Dose-dependent significant
increase in major extracranial
Anticoagulation slightly but signifi-
cantly increased symptomatic in-
Anticoagulation significantly reduced
DVT and symptomatic pulmonary emboli
No significant difference in the
proportion of people dead or depen-
Unfractionated
heparin,
23,748 people with
stroke, over 80% of the
Systematic
review,
[23]
haemorrhages during treat- tracranial haemorrhages during compared with placebo or no treatment dent in the treatment and control LMWH, hepari- data came from one un- search
ment period with anticoagu- treatment period compared with during the treatment period (DVT, 10 groups at the end of follow-up noids, oral anti- blinded factorial design date 2007,
24 RCTs lants compared with control
(18 RCTs; 22,255 people:
control (16 RCTs, 22,943 people:
168/11,701 [1.4%] with treatment
RCTs, 916 people at high risk of DVT
after their stroke, DVT: 69/456 [15%]
(more than 1 month after the
stroke, 8 RCTs, 22,125 people):
coagulants, or
specific throm-
RCT
[18]
comparing as-
pirin, subcutaneous hep-
143/11,255 [1.4%] with treat- v 54/11,242 [0.5%] with control; with treatment v 204/460 [44%] with 6698/11,269 (62%) with treatment bin inhibitors v arin, aspirin plus heparin,
ment v 42/11,000 [0.4%] with OR 2.55, 95% 1.95 to 3.33). The control; OR 0.21, 95% CI 0.15 to 0.29; v 6502/10,856 (60%) with control; placebo or no
treatment
or no treatment in people
with any severity of
stroke within 48 hours of
control; OR 2.99, 95% CI 2.24
to 3.99)
large trial of subcutaneous heparin
found that this effect was dose
dependent (symptomatic intracra-
pulmonary embolism, 14 RCTs:
69/11,470 [1%] for treatment v 104/1074
[10%] for control; OR 0.60, 95% CI 0.44
OR 0.99, 95% CI 0.93 to 1.04.
There was no clear short- or long-
term benefit of anticoagulants in stroke onset, usually after
nial haemorrhage by using medi- to 0.81). No RCT performed investiga- any pre-specified subgroups exclusion of haemor-
um-dose compared with low-dose tions in all people to rule out silent (stroke of presumed cardioembolic rhage by computerised
tomography scan heparin for 14 days: RRI 143%,
95% CI 82% to 204%; NNH 97,
95% CI 68 to 169)
events. The frequency of reported pul-
monary emboli was, low and varied
among RCTs, so there may have been
under-ascertainment
origin v others; different anticoagu-
lants)
Anticoagulants significantly
increased major extracranial
Anticoagulants (unfractionated
heparin and LMWH) significantly
Anticoagulants (unfractionated heparin
and LMWH) significantly reduced
No significant difference in death
or dependency at 3 to 6 months
Systemic anti-
coagulants
16,558 people treated
within 48 hours of acute
Systematic
review,
[24]
haemorrhage compared with increased symptomatic intracra- symptomatic DVT during the treatment between anticoagulants and an- (unfractionated ischaemic stroke, about search
aspirin (3 RCTs 11,721 peo- nial haemorrhage compared with period compared with aspirin (2 RCTs, tiplatelets (3 RCTs, 11,527 people: heparin and 88% of the data came date 2000,
4 RCTs ple: 52/6112 [0.9%] with
treatment v 25/5609 [0.4%]
aspirin (3 RCTs, 12,646 people:
75/6072 [1.2%] with treatment v
1933 people: 4/1217 [0.3%] with treat-
ment v 13/716 [1.8%] with control; OR
3802/5996 [63%] with treatment v
3430/5531 [62%] with control; OR
LMWH) v as-
pirin
from one unblinded facto-
rial design RCT
[18]
comparing aspirin, subcu- with control; OR 1.94, 95% CI
1.20 to 3.12)
31/5574 [0.6%] with control; OR
2.27, 95% CI 1.49 to 3.46). The
increase was greater with higher-
0.19, 95% CI 0.07 to 0.58). No signifi-
cant difference in symptomatic pul-
monary embolism (4 RCTs, 11,921
1.07, 95% CI 0.99 to 1.15). Results
were similar in the subgroup of
people with atrial fibrillation (2
taneous heparin, aspirin
plus heparin, or no treat-
dose compared with lower-dose people: 39/6112 [0.6%] with treatment RCTs, absolute numbers not report-
ed; OR 1.10, 95% CI 0.90 to 1.35)
ment in people with any
severity of stroke within
48 hours of stroke onset,
anticoagulants (high dose: abso-
lute figures not reported; OR 3.24,
v 42/5609 [0.7%] with control; OR 0.85,
95% CI 0.55 to 1.32)
usually after exclusion of 95% CI 2.09 to 5.04; low dose:
haemorrhage by comput-
erised tomography scan
absolute numbers not reported;
OR 1.29, 95% CI 0.72 to 2.32)
RCT does not assess intracranial haemorrhage separately, but
found a significant increase in the LMWH group compared with the
No significant difference between
LMWH and aspirin in DVT at 6 months
No significant difference between
LMWH and aspirin in survival with
LMWH versus
aspirin
353 Asian people with
large-artery occlusive
disease
1 RCT
[26]
aspirin group in combined haemorrhagic adverse effects (25/180
[14%] with LMWH v 15/173 [9%] with aspirin; OR 1.77, 95% CI
1.05 to 2.97; P = 0.031)
(1/180 [1%] with LMWH v 2/173 [1%]
with aspirin; P = 0.62)
a Barthel index score of 85 or
higher at 6 months (131/180 [73%]
with LMWH v 119/173 [69%] with
aspirin; OR 1.19, 95% CI 0.75 to
1.89)
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Unfractionated heparin plus
aspirin significantly increased
major extracranial haemor-
rhage compared with aspirin
alone (OR 3.79, 95% CI 2.39
to 6.01)
Unfractionated heparin plus as-
pirin significantly increased symp-
tomatic intracranial haemorrhage
compared with aspirin alone (OR
2.36, 95% CI 1.49 to 3.74)
No significant difference in pulmonary
embolism between unfractionated hep-
arin plus aspirin and aspirin alone (OR
0.58, 95% CI 0.34 to 1.00). The RCT
may have been underpowered to detect
a clinically important difference. DVT
not assessed
No significant difference in death
or dependency, either for all people
with stroke or for the subgroup of
people with atrial fibrillation (2
RCTs, 9639 people: 3002/4823
[62.2%] with treatment v 2998/4816
[62.3%] with control; OR 1.00, 95%
CI 0.92 to 1.09; people with atrial
fibrillation: absolute numbers not
reported; OR 1.00, 95% CI 0.92 to
1.09)
Unfractionated
heparin plus
aspirin v as-
pirin alone
9639 people Systematic
review,
search
date 2000,
2 RCTs
[24]
Number of events very low,
may be related to the fact that
people at high risk of bleeding
were excluded from the
RCTs, and so results should
be interpreted with caution (7
RCTs: 3012 people: 12/1570
[0.8%] with treatment v
2/1442 [0.1%] with control;
OR 3.79, 95% CI 1.30 to
11.06)
Number of events too small to as-
sess reliably
LMWHs or heparinoids significantly re-
duced DVT compared with unfractionat-
ed heparin (heparinoids v unfractionated
heparin; 5 RCTs, 705 people: 55/414
[13%] with treatment v 65/291 [22%]
with control; OR 0.52, 95% CI 0.35 to
0.79; LMWHs v unfractionated heparin;
7 RCTs, 2585 people: 140/1352 [10%]
with treatment v 206/1233 [17%] with
control; OR 0.55, 95% CI 0.44 to 0.70
Number of events too small to as-
sess reliably
LMWHs or
heparinoids v
unfractionated
heparin
3137 people with acute
ischaemic stroke
Systematic
review,
search
date 2007,
9 RCTs
[25]
DVT, deep venous thrombosis; LMWH, low molecular weight heparin
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TABLE GRADE evaluation of interventions for stroke management
Risk of death or dependency, quality of life, adverse effects Important outcomes
Comment GRADE
Effect
size
Direct-
ness
Consis-
tency Quality
Type of
evi-
dence Comparison Outcome
Number of studies
(participants)
What are the effects of specialised care in people with acute stroke?
Directness point deducted for large number of
interventions included in control group
Moderate 0 1 0 0 4 Organised inpatient stroke unit
care v conventional care
Risk of death or dependen-
cy
31(6936)
[7]
Quality points deducted for sparse data and for
RCT being underpowered to detect a clinically
important difference
Low 0 0 0 2 4 Integrated care pathways v con-
ventional multidisciplinary hospital
care
cy
1 (152)
[8]
Quality points deducted for sparse data and in-
complete reporting of results. Consistency point
Very low 0 0 1 2 4 Integrated care pathways v con-
ventional multidisciplinary hospital
care
Quality of life 1 (152)
[8]
deducted for different results at different time
points
Consistency point deducted for different results
for different subgroups
Moderate 0 0 1 0 4 Early supported discharge v con-
ventional hospital-based care
cy
12 (1659)
[9]
What are the effects of medical treatment in people with acute ischaemic stroke?
Quality point deducted for lack of blinding and
methodological issues in one large RCT contribut-
ing much of the data to the meta-analysis
Moderate 0 0 0 1 4 Aspirin v placebo Risk of death or dependen-
cy
4 (41,291)
[16]
Moderate 0 0 0 1 4 Aspirin plus heparin v aspirin
alone
cy
2 (9639)
[24]
Low 0 1 0 1 4 Systemic anticoagulants v place-
bo/no treatment
cy
8 (22,125)
[23]
ing much of the data to the meta-analysis. Direct-
ness point deducted for large number of interven-
tions used
Moderate 0 0 0 1 4 Systemic anticoagulants v aspirin Risk of death or dependen-
cy
4 (11,880)
[24] [26]
Directness points deducted for heterogeneous
results and for uncertainty about generalisability
Low 0 2 0 0 4 Any thrombolytic v no thromboly-
sis
cy
at least 14 RCTs (at
least 4807 people)
[28]
[29]
of results in people with most severe strokes,
and for large number of interventions used
Quality points deducted for sparse data and no
statistical comparison between groups
Moderate 0 0 0 2 4 Desmoteplase v placebo Risk of death or dependen-
cy
1 (186)
[31]
Quality point deducted for incomplete reporting
of results. Directness point deducted for uncer-
Low 0 1 0 1 4 Recombinant tissue plasminogen
activator v no thrombolysis
cy
7 (3651)
[28] [32]
tainty about generalisability of results in people
with most severe strokes
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Comment GRADE
Effect
size
Direct-
ness
Consis-
tency Quality
Type of
evi-
Number of studies
(participants)
of results. Directness point deducted for hetero-
geneous results and for uncertainty about gener-
alisability of results in people with mild or most
severe strokes
Low 0 1 0 1 4 Streptokinase v placebo Risk of death or dependen-
cy
4 (1292)
[30]
High 0 0 0 0 4 Calcium channel blockers v
placebo
cy
at least 28 RCTs (at
least 7522 people)
[42]
of results
Moderate 0 0 0 1 4 Citicoline v placebo Risk of death or dependen-
cy
4 (1652)
[45]
High 0 0 0 0 4 GABA agonists v placebo Risk of death or dependen-
cy
5 (3481)
[46] [47] [48]
of results
Moderate 0 0 0 1 4 Glycine antagonists (gavestinel)
v placebo
cy
10 (6922)
[49] [50] [51]
High 0 0 0 0 4 Lubeluzole v placebo Risk of death or dependen-
cy
At least 5 RCTs (at
least 3553 people)
[49]
[52]
of results
Moderate 0 0 0 1 4 Magnesium v placebo Risk of death or dependen-
cy
5 (2751)
[49] [53]
High 0 0 0 0 4 N-methyl-D-aspartate receptor
antagonists v placebo
cy
10 (6317)
[49]
High 0 0 0 0 4 5-hydroxytryptamine-2 serotoner-
gic antagonists (naftidrofuryl) v
placebo
cy
6 (1274)
[56]
Quality point deducted for incomplete reporting Moderate 0 0 0 1 4 Intercellular adhesion molecule-1
(ICAM-1) antibody (enlimomab) v
placebo
cy
1 (625)
[57]
Directness point deducted for large number of
interventions used
Moderate 0 1 0 0 4 Blood pressure reduction v place-
bo
cy
at least 9 RCTs (at
least 1067 people)
[63]
[65] [66]
What are the effects of decompressive hemicraniectomy in acute ischaemic stroke?
Quality points deducted for sparse data and
early discontinuation of studies
Low 0 0 0 2 4 Decompressive hemicraniectomy
v medical treatment
cy
3 (134)
[67] [68] [69]
Quality points deducted for sparse data and
early discontinuation of study
Low 0 0 0 2 4 Decompressive hemicraniectomy
v medical treatment
Quality of life 1 (64)
[69]
What are the effects of surgical treatment for intracerebral haematomas?
Consistency point deducted for different results
for different surgery types
Moderate 0 0 1 0 4 Surgical evacuation v medical
treatment
cy
11 (2167)
[71] [72]
Stroke management
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Comment GRADE
Effect
size
Direct-
ness
Consis-
tency Quality
Type of
evi-
Number of studies
(participants)
Type of evidence: 4 = RCT; 2 = Observational
Consistency: similarity of results across studies
Directness: generalisability of population or outcomes
Effect size: based on relative risk or odds ratio
Stroke management
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Search date June 2009

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