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Stroke managementSearch date June 2009Josef Alawneh, Philip Clatworthy, Rhiannon Morris, and Elizabeth Warburton

ABSTRACTINTRODUCTION: Stroke is the third most common cause of death in most developed countries. It is a worldwide problem; about 4.5 millionpeople 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 allacute strokes are ischaemic, usually resulting from thrombotic or embolic occlusion of a cerebral artery. The remainder are caused eitherby intracerebral or subarachnoid haemorrhage. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answerthe following clinical questions:What are the effects of specialised care in people with acute stroke? What are the effects of medical treatmentin people with acute ischaemic stroke? What are the effects of decompressive hemicraniectomy in acute ischaemic stroke? What are theeffects of surgical evacuation for intracerebral haematomas? We searched: Medline, Embase, The Cochrane Library, and other importantdatabases up to June 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date versionof 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 observationalstudies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: Inthis systematic review we present information relating to the effectiveness and safety of the following interventions: acute reduction in bloodpressure, 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-aspartateantagonists), 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

Neuroprotective agents (calcium channel blockers, citi-coline, GABA agonists, glycine antagonists, lubeluzole,magnesium, N-methyl-D-aspartate antagonists) . . . 9

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Specialised care (specialist stroke rehabilitation) 3

It is the third most common cause of death in most developing countries, with about 4.5 million people worldwidedying 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 rehabilitationseems more effective than conventional care at reducing death and dependency

after 1 year.

Aspirineffectively 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 alower risk of intra- and extracranial haemorrhage.

Thrombolysis(given within 3 hours of symptom onset) reduces death or dependency at 6 months in people withconfirmed 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

loweringin acute ischaemic stroke may actually lead to increased cerebral ischaemia.

Neuroprotective drugsdo not seem to significantly reduce the risk of poor outcome (including death) or to improveoutcome in people with ischaemic stroke.

In young people with malignant middle cerebral artery (MCA) infarction, decompressive hemicraniectomyis aneffective life-saving treatment.

In people with primary supratentorial haematomas, surgical evacuationmay 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 timesglobal, loss of cerebral function lasting over 24 hours or leading to death, with no apparent causeother than that of vascular origin.

[1]Ischaemic stroke is stroke caused by vascular insufficiency

(such as cerebrovascular thromboembolism) rather than by haemorrhage.

INCIDENCE/ Stroke is the third most common cause of death in most developed countries [2] It is a worldwide

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same study design criteria for inclusion as we did for benefits. In addition we use a regularsurveillance protocol to capture harms alerts from organisations such as the US Food and DrugAdministration (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 whenrelating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). Wehave performed a GRADE evaluation of the quality of evidence for interventions included in thisreview (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 definedpopulations of interest. These categorisations are not necessarily a reflection of the overallmethodological quality of any individual study, because the Clinical Evidencepopulation and outcomeof 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 dependencyOrganised inpatient stroke unit care compared with conventional careOrganised inpatient stroke unit care is moreeffective 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 integratedcare 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 careESD seems more effective atreducing 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


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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 ESDschemes significantly reduced death and dependency after stroke compared with usual care (seetable 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 ESDservice 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 (seereview 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 treatmentwithin a short time frame (3 hours if possible), it is applicable only to a small proportion of peoplewith stroke.

The first systematic review did not provide evidence about which aspects of organised inpatientstroke 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 therewas no significant difference in rates of death or dependency in units with semi-intensive monitoringcompared 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 strokeunits faired worse than those cared for on a dedicated stroke unit. However, only one RCT in thissystematic 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 unitsetting. However the duration of stay was calculated differently for many of the studies and soheterogeneity among results limits generalisability.

In an attempt to explain the reasons for improved outcome on dedicated stroke units a further


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Compared with systemic anticoagulationAspirin and systemic anticoagulants (unfractionated or low molecular weightheparin) given within 48 hours of ischaemic stroke are equally effective at 3 to 6 months at reducing death or depen-dency (moderate-quality evidence).

For GRADE evaluation of interventions for stroke management, see table , p 24 .

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 orno 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, aspirinplus 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 randomisedbefore CT scan if the stroke was very likely to be ischaemic on clinical grounds. Treatment durationvaried from 10 to 28 days. The review found that aspirin started within the first 48 hours of acuteischaemic stroke significantly reduced death or dependency at 6 months' follow-up (9285/20,647[45%] with aspirin v9529/20,644 [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: RR1.06, 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 extracranialhaemorrhages per 1000 people treated, but that these small risks were more than offset by thereductions 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:


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Systemic anticoagulants compared with aspirinSystemic anticoagulants (unfractionated or low molecular weightheparin) and aspirin given within 48 hours of ischaemic stroke are equally effective at 3 to 6 months at reducingdeath or dependency (moderate-quality evidence).

Aspirin plus heparin compared with aspirin aloneAspirin plus unfractionated or low molecular weight heparin givenwithin 48 hours of ischaemic stroke onset is no more effective at reducing death or dependency (moderate-qualityevidence).

NoteSystemic 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 betweenanticoagulants 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 betweenLMWH and aspirin in a combined outcome defined as survival with a Barthel indexscore 85 orgreater 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 betweenaspirin 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[25]


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Alternative treatments to prevent deep venous thrombosis and pulmonary embolism after acuteischaemic stroke include aspirin and compression stockings.The evidence relating to these willbe reviewed in future Clinical Evidenceupdates. One large RCT found that high-dose unfractionatedheparin for stroke management resulted in worse outcomes compared with low-dose unfractionated

heparin. [18]

OPTION THROMBOLYSIS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Risk of death or dependencyAny thrombolytic compared with placebo/no thrombolysisThrombolytics (streptokinase, recombinant tissue plasmino-gen activators, urokinase, and pro-urokinase) given soon after onset of confirmed ischaemic stroke may be moreeffective at reducing death or dependency but may increase mortality at 3 to 6 months (low-quality evidence).

Desmoteplase compared with placeboDesmoteplase given soon after onset of stroke may be no more effective atachieving a good-clinical-outcome measure (defined as a composite of improvement in National Institutes of HealthStroke Scale [NIHSS] score of 8 points or greater or an NIHSS score of 1 point or less, a modified Rankin scalescore of 02 points, and a Barthel index of 75100) (low-quality evidence).

Recombinant tissue plasminogen activator compared with placebo/no thrombolysisRecombinant tissue plasminogenactivators given soon after onset of stroke may be more effective at reducing death or dependency (low-quality evi-dence).

Streptokinase compared with placebo/no thrombolysisStreptokinase 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).

NoteThrombolysis 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:


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of 1 point or less, a modified Rankin scale score of 02 points, and a Barthel indexof 75100) atday 90 (27/57 [47%] with desmoteplase 90 micrograms/kg v24/66 [36%] with desmoteplase 125micrograms/kg v29/63 [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 nothrombolysis (6 RCTs; 2830 people: 729/1431 [51%] with rtPA v789/1399 [56%] with no thrombol-ysis; OR 0.80, 95% CI 0.69 to 0.93; P = 0.003). The second subsequent RCT (821 people withacute 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 scoreof 0 or 1) compared with placebo after 90 days' follow-up (219/418 [52%] with alteplase v182/403[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 samestreptokinase RCTs as were identified by the first review, but found no significant difference betweenstreptokinase 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 inthe 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 fromintracranial haemorrhage.

[29]

Desmoteplase versus placebo/no thrombolysis:


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systematic review (search date 2003) concluded that current RCT evidence regarding the bestdosage, 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. Anearlier preliminary pooling of three RCTs (1734 people) suggested that rtPA given between 3 and6 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 between3 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 identificationof 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 to4.5 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 arewarranted, as are trials aimed at determining the benefit of thrombolysis within the 3 to 6 hourwindow, 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 frameto ensure that as many eligible people as possible receive treatment. Problems over recognitionof stroke in the community, and failure to admit people quickly to stroke centres, mean that mostarrive too late to be considered for thrombolysis, although about one in four people who arrivewithin 3 hours of stroke are suitable for treatment.We found two systematic reviews (search dates2001

[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, 6345or more people with acute ischaemic stroke) found that interventions that improved delivery ofthrombolysis were: education programmes to raise public awareness of stroke symptoms; training

programmes for paramedics to impro e diagnostic skills and hasten rapid triage to hospital and


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Magnesium compared with placeboMagnesium 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 placeboNaftidrofuryl is no more effectiveat reducing death, dependence, or disability in people with acute ischaemic or haemorrhagic stroke (high-qualityevidence).

Intercellular adhesion molecule-1 (ICAM-1) antibody (enlimomab) compared with placeboEnlimomab given within6 hours of acute ischaemic stroke seems no more effective at reducing mortality and seems less effective at reducingdisability (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 channelblockers 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 channelblockers v1256/3052 [41%] with placebo; RR 1.04, 95% CI 0.98 to 1.09; death: 28 RCTs, 7522people: 911/4145 [22%] with calcium channel blockers v699/3377 [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 moderateto 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 3months compared with placebo (25% with citicoline v20% with placebo; OR 1.33, 95% CI 1.10 to1.62; P = 0.0034, absolute numbers not reported). However, it found no significant difference in

mortalit bet een citicoline and placebo (19% ith citicoline 18% ith placebo reported as not


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(1080/1842 [59%] with lubeluzole v993/1711 [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 betweenlubeluzole (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 v920/1667 [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 v33/74 [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 NMDAreceptor 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 ordependence (1674/3336 [50%] with NMDA receptor antagonists v1453/2981 [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 ofpeople 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 v37/286[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 v19% 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 ischaemicor 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

d d /di bilit ( t lit 6 RCT 1274 l 130/638 [20 4%] ith ftid f l


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Glycine antagonists (gavestinel) versus placebo:The review gave no information on adverse effects.

[49]

Lubeluzole versus placebo:

The first review gave no information on adverse effects. [49] The second review found that, at anydose, lubeluzole was associated with a significant increase in the risk of having a heart conductiondisorder (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 v156/1610 [10%] with placebo; RR 1.23, 95% CI1.05 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 scheduledfollow-up (5 RCTs, 3501 people: 126/1822 [7%] with lubeluzole v91/1679 [5%] with placebo; RR1.26, 95% CI 0.97 to 1.64).

[52]

Magnesium versus placebo:The review gave no information on adverse effects. [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:The review gave no information on adverse effects.

[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 naftidrofuryland placebo in minor adverse effects, although the incidence of adverse effects was higher withnaftidrofuryl (23/243 [9%] with naftidrofuryl v12/249 [5%] with placebo; RR 1.86, 95% CI 0.95 to3.64).

[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 therisk of serious adverse effects (9/216 [4%] with naftidrofuryl v6/226 [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

li b 30% ith l b b l t b t t d t ti ti l i ifi t d)


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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 90days (disability; median change in NIHSS score from baseline: 6.0 with DP-b99 v5.0 withplacebo; P = 0.56; mortality: 12/75 [16%] with DP-b99 v15/75 [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 v28/75 [37%] withplacebo; P = 0.32).

[62]

OPTION BLOOD PRESSURE REDUCTION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Risk of death or dependencyCompared with placeboAntihypertensive 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 versusplacebo (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 orcombined antihypertensives (1 RCT, 203 people). One RCT (9 people) investigated the effect ofphenylephrine 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 ordependency at follow-up (14 days to 3 months in 5 RCTs, not given in 2 RCTs) (7 RCTs, 586people: 152/309 [49%] with interventions aimed at lowering blood pressure v129/277 [47%] withplacebo; OR 1.05, 95% CI 0.76 to 1.47). It found no significant difference between groups in casefatality within 1 month (proportion of people who died owing to stroke: 11/166 [7%] with interventionsaimed at lowering blood pressure v14/195 [7%] with placebo; RR 0.92, 955 CI 0.39 to 2.16).The

th l d d th t th i i ffi i t id t l t th ff t f lt i bl d


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The first additional RCT suggested that people treated with antihypertensive drugs may have aworse 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 propranololand placebo (9 with atenolol v5 with propranolol v5 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 (statisticalanalysis 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 v33 with lisinopril v35with placebo; RR 0.91 [active treatment vplacebo], 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 relationbetween changes in blood pressure and clinical outcome.

[63]

The authors of the systematic review only included RCTs with the specific aim of altering bloodpressure, as they felt that there were methodological differences between studies that aimed toalter blood pressure and those that may, or may not, have measured blood pressure as part oftheir 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]

Calciumchannel blockers are both antihypertensive agents and neuroprotective agents.They are consideredspecifically in the neuroprotective agents, p 9 option.

QUESTION What are the effects of decompressive hemicraniectomy in acute ischaemic stroke?

OPTION DECOMPRESSIVE HEMICRANIECTOMY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . New

Risk of death or dependencyCompared with optimum medical careDecompressive hemicraniectomy may be more effective at reducing mortalityat 30 days to 1 year.We don't know whether it is more effective at reducing disability (low quality-evidence).

Quality of lifeCompared with optimum medical careWe don't know whether decompressive hemicraniectomy is more effective ati i lit f lif ( d b SF 36) t 1 (l lit id )


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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 earlybased on a calculation which suggested it was underpowered to show a 20% difference for theprimary 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 significantlyimproved survival compared with conservative treatment alone at 30 days (15/17 [88%] with hem-icraniectomy plus conservative treatment v7/15 [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 perthe 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-occupyingoedema on CT) compared surgical decompression within 99 hours after the onset of symptomsversus best medical treatment.

[69]The primary outcome measure was the mRS at 1 year, which

was dichotomised between good (0

3) and poor (4

6). The RCT found no significant differencebetween groups with respect to the primary outcome (proportion of people with a poor outcome:24/32 [75%] with surgical v24/32 [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 itwas highly likely to be underpowered to find a statistically significant difference between groups inthe primary outcome with the planned sample size (112 people).The RCT found that surgicaltreatment significantly reduced mortality compared with the best medical treatment at 1 year (7/32[22%] with surgical v19/32 [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 v36 with best medical care;mean difference 8, 95% CI 14 to 1; P = 0.02). It found no significant differences between thetwo treatment groups in the mental summary score of the SF-36 score, mood, or proportion ofpeople (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]


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The review compared surgery plus medical versus medical treatment. The primary outcome wasdeath or dependency. It found that surgery plus conservative care significantly reduced death ordependency (defined as assistance from other people for their activities of daily living after 36months) compared with conservative care alone (9 RCTs, 1994 people: 628/996 [63%] with surgery

plus conservative care v705/998 [71%] with conservative care alone; OR 0.71, 95% CI 0.58 to0.88; P = 0.001) and death at final follow-up (36 months) (10 RCTs, 2059 people: 278/1030 [17%]with surgery plus conservative care v346/1029 [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 assessedaccording to type of surgery. It found that stereotactic or endoscopic surgery significantly reduceddeath or dependency compared with conservative care (4 RCTs, 566 people: 172/276 [62%] withstereotactic or endoscopic surgery plus conservative care v206/290 [71%] with conservative carealone; OR 0.66, 95% CI 0.46 to 0.96), but there was no significant difference between craniotomyplus conservative care and conservative care alone (4 RCTs, 769 people: 281/375 [75%] withcraniotomy plus conservative care v309/394 [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 haemorrhagegreater 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 (GOSgreater than 3: 33% with surgery v9% with non-surgical management; P = 0.002; absolute numbersnot reported).

[72]However, the RCT found no significant difference between groups in mortality

at 1 year (26/54 [48%] with surgical management v31/54 [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 ventricularshunting 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]

I l ith i f t t i l h t


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AspirinOne systematic review updated.[16]

It now includes one more small RCT, but the conclusion is unchanged.Categorisation unchanged (Beneficial).Specialised careOne 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 comparedwith usual care. Categorisation unchanged (Beneficial).Systemic anticoagulationOne 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).Thrombolysis Two 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-outcomemeasure 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 90days versus placebo.

[32]Categorisation unchanged (Trade-off between benefits and harms).

Blood pressure reductionOne systematic review [63] updated, it now includes one subsequent RCT previouslyreported separately in this Clinical Evidencereview. The review found no significant difference between treatmentaimed at lowering blood pressure in acute stroke versus placebo, in death or dependency at final follow-up or in casefatality 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 Likelyto be ineffective or harmful to Unlikely to be beneficial.EvacuationOne systematic review updated.

[71]It now includes one RCT previously reported separately in this

Clinical Evidencereview 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 dependencycompared with conservative care alone in people with supratentorial intracerebral haemorrhage. However, it gaveno information on harms of evacuation.This change was enough to upgrade the categorisation in this Clinical Evidencereview 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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46. Ricci S, Celani MG, Cantisani AT, et al. Piracetam for acute ischaemic stroke.In: The Cochrane Library, Issue 2, 2009. Chichester, UK: John Wiley & Sons,Ltd. Search date 2005.[PubMed]

47. Wahlgren NG, Ranasinha KW, Rosolacci T, et al. Clomethiazole acute strokestudy (CLASS): results of a randomised, controlled trial of clomethiazole versusplacebo in 1360 acute stroke patients. Stroke1999;30:2128.[PubMed]

48. Lyden P, Shuaib A, Ng K, et al. Clomethiazole Acute Stroke Study in IschemicStroke (CLASS-I) final results. Stroke2002;33:122129.[PubMed]

49. Muir KW, Lees KR. Excitatory amino acid antagonists for acute stroke. In: TheCochrane Library, Issue 2, 2009. Chichester, UK: John Wiley & Sons, Ltd. Searchdate 2001.[PubMed]

50. Lees K, Asplund K, Carolei A, et al. Glycine antagonist (gavestinel) in neuropro-tection (GAIN International) in people with acute stroke: a randomised controlledtrial. Lancet2000;355:19491954.[PubMed]

54. Davis S, Lees K, Albers G, et al, for the ASSIST Investigators. Selfotel in acuteischemic stroke. Possible neurotoxic effects of an NMDA antagonist. Stroke2000;31:347354.[PubMed]

55. Albers GW, Goldstein LB, Hall D, et al. Aptiganel hydrochloride in acute ischemicstroke. A randomised controlled trial. JAMA2001;286:26732682.[PubMed]

56. Leonardi-Bee J, Steiner T, Bath-Hextall FJ. Naftidrofuryl for acute stroke. In:TheCochrane Library, Issue 2, 2009. Chichester, UK: John Wiley & Sons, Ltd. Searchdate 2006.[PubMed]

57. Enlimomab Acute Stroke Trial Investigators. Use of anti-ICAM-1 therapy in is-chemic stroke: results of the Enlimomab Acute Stroke Trial. Neurology2001;57:14281434.[PubMed]

58. Ferguson KN, Kidwell CS, Starkman S, et al. Hyperacute treatment initiation inneuroprotective agent stroke trials. J Stroke Cerebrovasc Dis2004;13:109112.

59. The Tirilazad International Steering Committee.Tirilazad for acute ischaemicstroke. In:The Cochrane Library, Issue 2, 2009. Chichester, UK: John Wiley &Sons, Ltd. Search date 2001.[PubMed]

60. Lees KR, Zivin JA, Ashwood T, et al. NXY-059 for acute ischaemic stroke.NEngl J Med2006;354:588600.[PubMed]

61. Lees KR, Davalos A, Davis SM, et al. Additional outcomes and subgroup analyses

of NXY-059 for acute ischemic stroke in the SAINT I tr ial. Stroke2006;37:29702978.[PubMed]

62. Diener HC, Schneider D, Lampl Y, et al. DP-b99, a membrane-activated metalion chelator, as neuroprotective therapy in ischemic stroke.Stroke2008;39:17741778.[PubMed]

63. Geeganage C, Bath PMW. Interventions for deliberately altering blood pressurein acute stroke. In: The Cochrane Library, Issue 2, 2009. Chichester, UK: JohnWiley & Sons, Ltd. Search date 2007.[PubMed]

64. Wahlgren NG, MacMahon DG, DeKeyser J, et al. Intravenous nimodipine westEuropean stroke trial (INWEST) of nimodipine in the treatment of acute ischaemicstroke.Cerebrovasc Dis1994;4:204210.

65. Barer DH, Cruickshank JM, Ebrahim SB, et al. Low dose beta blockade in acutestroke (BEST trial): an evaluation.BMJ1988;296:737741.[PubMed]

66. Potter JF, Robinson TG, Ford GA, et al. Controlling hypertension and hypotensionimmediately post-stroke (CHHIPS): a randomised, placebo-controlled, double-blind pilot trial. Lancet Neurol2009;8:4856.[PubMed]

67. Vahedi K, Vicaut E, Mateo J, et al. Sequential-design, multicenter, randomized,controlled trial of early decompressive craniectomy in malignant middle cerebralartery infarction (DECIMAL Trial). Stroke2007;38:25062517.[PubMed]

68. Juttler E, Schwab S, Schmiedek P, et al. Decompressive Surgery for the Treat-ment of Malignant Infarction of the Middle Cerebral Artery (DESTINY): a random-ized, controlled trial. Stroke2007;38:25182525.[PubMed]

69. Hofmeijer J, Kappelle LJ, Algra A, et al. Surgical decompression for space-occu-pying cerebral infarction (the Hemicraniectomy After Middle Cerebral Artery in-farction with Life-threatening Edema Trial [HAMLET]): a multicentre, open, ran-domised trial. Lancet Neurol2009;8:326333.[PubMed]

70. Vahedi K, Hofmeijer J, Juettler E, et al. Early decompressive surgery in malignanti f ti f th iddl b l t l d l i f th d i d


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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 isfunded 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 ajudgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit andharms. 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 researchwe strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, thecategories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimatelyit is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullestextent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to anyperson 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.

CommentsResultsComparisonParticipantsMethodsRef

The specialised stroke rehabilitationunit 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 analysisnot reportedDeath 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 reportedDeath or dependency at 5 years: 2 RCTs; 223/286 (78%) with organ-ised stroke unit care v214/249 (86%) with alternative care; OR 0.59,95% CI 0.38 to 0.92Death or institutional care at 5 years:2 RCTs, 172/286 (60%) withorganised stroke unit care v178/249 (71%) with alternative care; OR0.62, 95% CI 0.43 to 0.89Death or dependency at 10 years: 2 RCTs, 249/286 (87%) with organ-ised stroke unit care v224/249 (90%) with alternative care; OR 0.77,95% CI 0.45 to 1.31Death or institutional care, 10 years after stroke: 2 RCTs, 220/286(77%) with organised stroke unit care v214/249 (86%) with alternativecare; OR 0.57, 95% CI 0.37 to 0.88

Stroke unit care valternative,less-organised care

6936 people with stroke,primarily acute ischaemicstroke

Systematic review,search date 2006, 31RCTs

[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 v920/1629 (56%) with general medical ward; OR0.83, 95% CI 0.72 to 0.96

Stroke unit care vgeneral medi-cal ward

3285 people with stroke,primarily acute ischaemicstroke

Subgroup analysis, 13RCTs

Death or dependency at median follow-up of 1 year: 233/340 (69%)with mobile stroke team v250/359 (70%) with general medical ward;OR 0.96, 95% CI 0.69 to 1.34

Mobile stroke team vgeneralmedical ward

699 people with stroke, pri-marily acute ischaemicstroke


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 pathwaysv50/76 (65%) with standard care; OR 1.36, 95% CI 0.68 to 2.72Death alone at 6 months:10/76 (13%) with care pathways v6/76 (8%)with standard care; OR 1.77, 95% CI 0.61 to 5.14Quality of life at 6 months:median EuroQol score at 6 months: 63with care pathways v72 with standard care; P less than 0.005

Care based on in-hospital carepathways vstandard care

152 people with all types ofstroke

Systematic review,search date 2003, 1RCT

[8]

An ESD intervention was defined by thereview authors as "one that aims to ac-

Death or dependency at end of scheduled follow-up (median 6months):12 RCTs 375/835 (45%) with ESD v413/824 (50%) withconventional care; OR 0.81, 95% CI 0.67 to 0.99; P = 0.04

EDS services vconventional care1659 people with strokeadmitted to hospital

Systematic review,search date not report-ed, 12 RCTs

[9]

celerate discharge from hospital withthe provision of rehabilitation and sup-port in the community setting".The in-terventions included (7 RCTs): singlemultidisciplinary ESD team co-ordinatedhospital discharge and provided rehabil-itation at home (3 RCTs): ESD teamco-ordinated discharge and providedimmediate post-discharge care, but notongoing rehabilitation (2 RCTs): unco-ordinated community services or inputfrom healthcare volunteers

BMJ Publishing Group Ltd 2010. All rights reserved. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

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CommentsResultsComparisonParticipantsMethodsRef

Death or dependency at end of scheduled follow-up (median 6months):7 RCTs; 200/426 (47%) with ESD v228/416 (55%) with con-ventional care; OR 0.71, 95% CI 0.54 to 0.94

ESD team c o-ordinated hospitaldischarge and provided rehabili-tation at home vconventionalcare

842 people with stroke ad-mitted to hospital


Death or dependency at end of scheduled follow-up (median 6months):3 RCTs; 99/233 (42%) with ESD v113/231 (49%) with con-ventional care; OR 0.77, 95% CI 0.54 to 1.11

ESD team co-ordinated dis-charge and provided immediatepost-discharge care, but not on-going rehabilitation services vconventional care



Death or dependency at end of scheduled follow-up (median 6months):2 RCTs; 79/176 (45%) with ESD v72/177 (41%) with conven-tional care; OR 1.23, 95% CI 0.79 to 1.91

Unco-ordinated community ser-vices or input from healthcarevolunteer vconventional care



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 intracranialhaemorrhage

DVT and pulmonary embolismDeath or dependencyComparisonParticipantsMethodsRef

Dose-dependent significantincrease in major extracranial

Anticoagulation slightly but signifi-cantly increased symptomatic in-

Anticoagulation significantly reducedDVT and symptomatic pulmonary emboli

No significant difference in theproportion of people dead or depen-

Unfractionatedheparin,

23,748 people withstroke, over 80% of the

Systematicreview,

[23]

haemorrhages during treat-tracranial haemorrhages duringcompared with placebo or no treatmentdent in the treatment and controlLMWH, hepari-data came from one un-searchment period with anticoagu-treatment period compared withduring the treatment period (DVT, 10groups at the end of follow-upnoids, oral anti-blinded factorial designdate 2007,

24 RCTs lants compared with control(18 RCTs; 22,255 people:control (16 RCTs, 22,943 people:168/11,701 [1.4%] with treatmentRCTs, 916 people at high risk of DVTafter their stroke, DVT: 69/456 [15%](more than 1 month after thestroke, 8 RCTs, 22,125 people):coagulants, orspecific throm-RCT

[18]

comparing as-pirin, subcutaneous hep-143/11,255 [1.4%] with treat-v54/11,242 [0.5%] with control;with treatment v204/460 [44%] with6698/11,269 (62%) with treatmentbin inhibitors varin, aspirin plus heparin,ment v42/11,000 [0.4%] withOR 2.55, 95% 1.95 to 3.33).Thecontrol; OR 0.21, 95% CI 0.15 to 0.29;v6502/10,856 (60%) with control;placebo or no

treatmentor no treatment in peoplewith any severity ofstroke within 48 hours of

control; OR 2.99, 95% CI 2.24to 3.99)

large trial of subcutaneous heparinfound that this effect was dosedependent (symptomatic intracra-

pulmonary embolism, 14 RCTs:69/11,470 [1%] for treatment v104/1074[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 instroke onset, usually after

nial haemorrhage by using medi-to 0.81). No RCT performed investiga-any pre-specified subgroupsexclusion of haemor-um-dose compared with low-dosetions in all people to rule out silent(stroke of presumed cardioembolicrhage 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 variedamong RCTs, so there may have beenunder-ascertainment

origin vothers; different anticoagu-lants)

Anticoagulants significantlyincreased major extracranial

Anticoagulants (unfractionatedheparin and LMWH) significantly

Anticoagulants (unfractionated heparinand LMWH) significantly reduced

No significant difference in deathor dependency at 3 to 6 months

Systemic anti-coagulants

16,558 people treatedwithin 48 hours of acute

Systematicreview,

[24]

haemorrhage compared withincreased symptomatic intracra-symptomatic DVT during the treatmentbetween anticoagulants and an-(unfractionatedischaemic stroke, aboutsearch

aspirin (3 RCTs 11,721 peo-nial haemorrhage compared withperiod compared with aspirin (2 RCTs,tiplatelets (3 RCTs, 11,527 people:heparin and88% of the data camedate 2000,4 RCTs ple: 52/6112 [0.9%] withtreatment v25/5609 [0.4%]

aspirin (3 RCTs, 12,646 people:75/6072 [1.2%] with treatment v

1933 people: 4/1217 [0.3%] with treat-ment v13/716 [1.8%] with control; OR

3802/5996 [63%] with treatment v3430/5531 [62%] with control; OR

LMWH) vas-pirin

from one unblinded facto-rial design RCT

[18]

comparing aspirin, subcu- with control; OR 1.94, 95% CI1.20 to 3.12)

31/5574 [0.6%] with control; OR2.27, 95% CI 1.49 to 3.46).Theincrease 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). Resultswere similar in the subgroup ofpeople with atrial fibrillation (2

taneous heparin, aspirinplus heparin, or no treat-

dose compared with lower-dosepeople: 39/6112 [0.6%] with treatmentRCTs, absolute numbers not report-ed; OR 1.10, 95% CI 0.90 to 1.35)

ment in people with anyseverity of stroke within48 hours of stroke onset,

anticoagulants (high dose: abso-lute figures not reported; OR 3.24,

v42/5609 [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, butfound a significant increase in the LMWH group compared with the

No significant difference betweenLMWH and aspirin in DVT at 6 months

No significant difference betweenLMWH and aspirin in survival with

LMWH versusaspirin

353 Asian people withlarge-artery occlusivedisease

1 RCT[26]

aspirin group in combined haemorrhagic adverse effects (25/180[14%] with LMWHv15/173 [9%] with aspirin; OR 1.77, 95% CI

1.05 to 2.97; P = 0.031)

(1/180 [1%] with LMWH v2/173 [1%]with aspirin; P = 0.62)

a Barthel index score of 85 orhigher at 6 months (131/180 [73%]

with LMWH v 119/173 [69%] withaspirin; OR 1.19, 95% CI 0.75 to1.89)




23/26

Unfractionated heparin plusaspirin significantly increasedmajor extracranial haemor-rhage compared with aspirinalone (OR 3.79, 95% CI 2.39to 6.01)

Unfractionated heparin plus as-pirin significantly increased symp-tomatic intracranial haemorrhagecompared with aspirin alone (OR2.36, 95% CI 1.49 to 3.74)

No significant difference in pulmonaryembolism between unfractionated hep-arin plus aspirin and aspirin alone (OR0.58, 95% CI 0.34 to 1.00).The RCTmay have been underpowered to detecta clinically important difference. DVTnot assessed

No significant difference in deathor dependency, either for all peoplewith stroke or for the subgroup ofpeople with atrial fibrillation (2RCTs, 9639 people: 3002/4823[62.2%] with treatment v2998/4816[62.3%] with control; OR 1.00, 95%CI 0.92 to 1.09; people with atrialfibrillation: absolute numbers notreported; OR 1.00, 95% CI 0.92 to1.09)

Unfractionatedheparin plusaspirin vas-pirin alone

9639 peopleSystematicreview,searchdate 2000,2 RCTs

[24]

Number of events very low,may be related to the fact thatpeople at high risk of bleedingwere excluded from theRCTs, and so results shouldbe interpreted with caution (7RCTs: 3012 people: 12/1570[0.8%] with treatment v2/1442 [0.1%] with control;OR 3.79, 95% CI 1.30 to11.06)

Number of events too small to as-sess reliably

LMWHs or heparinoids significantly re-duced DVT compared with unfractionat-ed heparin (heparinoids vunfractionatedheparin; 5 RCTs, 705 people: 55/414[13%] with treatment v65/291 [22%]with control; OR 0.52, 95% CI 0.35 to0.79; LMWHs vunfractionated heparin;7 RCTs, 2585 people: 140/1352 [10%]with treatment v206/1233 [17%] withcontrol; OR 0.55, 95% CI 0.44 to 0.70

Number of events too small to as-sess reliably

LMWHs orheparinoids vunfractionatedheparin

3137 people with acuteischaemic stroke

Systematicreview,searchdate 2007,9 RCTs

[25]

DVT, deep venous thrombosis; LMWH, low molecular weight heparin




24/26

TABLE GRADE evaluation of interventions for stroke management

Risk of death or dependency, quality of life, adverse effectsImportant outcomes

CommentGRADEEffectsize

Direct-ness

Consis-tencyQuality

Type ofevi-

denceComparisonOutcomeNumber of studies

(participants)

What are the effects of specialised care in people with acute stroke?

Directness point deducted for large number ofinterventions included in control group

Moderate01004Organised inpatient stroke unitcare vconventional care

Risk of death or dependen-cy

31(6936)[7]

Quality points deducted for sparse data and forRCT being underpowered to detect a clinicallyimportant difference

Low00024Integrated care pathways vcon-ventional multidisciplinary hospitalcare


1 (152)[8]

Quality points deducted for sparse data and in-complete reporting of results. Consistency point

Very low00124Integrated care pathways vcon-ventional multidisciplinary hospitalcare

Quality of life1 (152)[8]

deducted for different results at different timepoints

Consistency point deducted for different resultsfor different subgroups

Moderate00104Early supported discharge vcon-ventional hospital-based care


12 (1659)[9]

What are the effects of medical treatment in people with acute ischaemic stroke?

Quality point deducted for lack of blinding andmethodological issues in one large RCT contribut-ing much of the data to the meta-analysis

Moderate00014Aspirin vplaceboRisk of death or dependen-cy

4 (41,291)[16]


Moderate00014Aspirin plus heparin vaspirinalone


2 (9639)[24]

Quality point deducted for lack of blinding andmethodological issues in one large RCT contribut-

Low01014Systemic anticoagulants vplace-bo/no treatment


8 (22,125)[23]

ing much of the data to the meta-analysis. Direct-ness point deducted for large number of interven-tions used


Moderate00014Systemic anticoagulants vaspirinRisk of death or dependen-cy

4 (11,880)[ 24 ] [26 ]

Directness points deducted for heterogeneousresults and for uncertainty about generalisability

Low02004Any thrombolytic vno thromboly-sis


at least 14 RCTs (atleast 4807 people)

[28]

[29]of results in people with most severe strokes,

and for large number of interventions usedQuality points deducted for sparse data and nostatistical comparison between groups

Moderate00024Desmoteplase vplaceboRisk of death or dependen-cy

1 (186)[31]

Quality point deducted for incomplete reportingof results. Directness point deducted for uncer-

Low01014Recombinant tissue plasminogenactivator vno thrombolysis


7 (3651)[ 28 ] [ 32 ]

tainty about generalisability of results in peoplewith most severe strokes




25/26



Direct-ness

Consis-tencyQuality

Type ofevi-


(participants)

Quality point deducted for incomplete reportingof results. Directness point deducted for hetero-geneous results and for uncertainty about gener-alisability of results in people with mild or mostsevere strokes

Low01014Streptokinase vplaceboRisk of death or dependen-cy

4 (1292)[30]

High00004Calcium channel blockers vplacebo



[42]

Quality point deducted for incomplete reportingof results

Moderate00014Citicoline vplaceboRisk of death or dependen-cy

4 (1652)[45]

High00004GABA agonists vplaceboRisk of death or dependen-cy

5 (3481)[46] [47] [48]


Moderate00014Glycine antagonists (gavestinel)vplacebo


10 (6922)[49] [50] [51]

High00004Lubeluzole vplaceboRisk of death or dependen-cy

At least 5 RCTs (atleast 3553 people)

[49]

[52]


Moderate00014Magnesium vplaceboRisk of death or dependen-cy

5 (2751)[ 49 ] [ 53 ]

High00004N-methyl-D-aspartate receptorantagonists vplacebo


10 (6317)[49]

High000045-hydroxytryptamine-2 serotoner-gic antagonists (naftidrofuryl) vplacebo


6 (1274)[56]

Quality point deducted for incomplete reportingModerate00014Intercellular adhesion molecule-1(ICAM-1) antibody (enlimomab) vplacebo


1 (625)[57]

Directness point deducted for large number ofinterventions used

Moderate01004Blood pressure reductionvplace-bo



[63]

[ 65 ] [ 66 ]

What are the effects of decompressive hemicraniectomy in acute ischaemic stroke?

Quality points deducted for sparse data andearly discontinuation of studies

Low00024Decompressive hemicraniectomyvmedical treatment


3 (134)[67] [68] [69]

Quality points deducted for sparse data andearly discontinuation of study

Low000

24Decompressive hemicraniectomyvmedical treatment

Quality of life1 (64) [69]

What are the effects of surgical treatment for intracerebral haematomas?

Consistency point deducted for different resultsfor different surgery types

Moderate00104Surgical evacuation vmedicaltreatment


11 (2167)[ 71 ] [72 ]




26/26



Direct-ness

Consis-tencyQuality

Type ofevi-


(participants)

Type of evidence: 4 = RCT; 2 = ObservationalConsistency: similarity of results across studiesDirectness: generalisability of population or outcomesEffect size: based on relative risk or odds ratio



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