Singapore Ministry of Health Clinical Practice Guidelines on Stroke and Transient Ischemic Attacks

Abstract

The primary aim of these guidelines is to assist individual clinicians, hospital departments, and hospital administrators to produce local protocols for the:

assessment, investigation and immediate management of individuals with a transient ischemic attack or acute stroke (other than sub-arachnoid hemorrhage), and

secondary prevention and risk factor management following a transient ischemic attack or acute stroke.

The secondary aim of these guidelines is to suggest methods for implementation and clinical audit. The workgroup preparing these guidelines was formed by the Ministry of Health, Singapore. It comprised healthcare workers from relevant specialties, family medicine, nursing, occupational therapy, and a lay patient advocate. The Scottish Intercollegiate Guidelines Network's Clinical Practice Guidelines on the Management of Patients with Stroke were reviewed, updated, and modified to meet local needs. The final guidelines are made up of evidence-based recommendations covering the following areas – assessment, investigation, immediate management, secondary prevention, rehabilitation, and implications for service delivery. The guidelines were sent to professional organizations for comments and endorsements. The final version was circulated to all medical practitioners in Singapore. It is hoped that the guidelines will improve the care of patients with stroke and transient ischemic attack. Clinical quality improvement measures are proposed.

Keywords

clinical practice guidelines stroke transient ischemic attack

Introduction

Stroke is a major cause of death, disability, and hospitalization in Singapore (1). Cerebral infarction accounts for 74%, primary intracerebral hemorrhage 24%, and sub-arachnoid hemorrhage 2% (2). Heavily subsided, accessible healthcare is provided by a network of public sector hospitals and polyclinics scattered throughout the island. Private practitioners provide 80% of primary healthcare services, while government polyclinics provide the remaining 20%. However, public hospitals provide 80% of the more expensive hospital-care with the remaining 20% being provided by private hospital care (3).

Scope of the guidelines

These guidelines address the assessment, investigations, immediate management, and secondary prevention of stroke and transient ischemic attack (TIA). This paper is a summary of the evidence behind the recommendations made in the guidelines; the recommendations are reproduced in full: Tables 1 –6.

Table 1a

Levels of evidence

Level	Type of Evidence
1⁺⁺	High-quality meta-analyses, systematic reviews of randomised controlled trials (RCTs), or RCTs with a very low risk of bias.
1⁺	Well-conducted meta-analyses, systematic reviews of RCTs or RCTs with a low risk of bias.
1⁻	Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias
2⁺⁺	High-quality systematic reviews of case–control or cohort studies. High quality case–control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal
2⁺	Well-conducted case–control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal
2⁻	Case–control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal
3	Nonanalytic studies, e.g. case reports, case series
4	Expert opinion

Table 1b

Grades of recommendations

Grade	Recommendation
A	At least one meta-analysis, systematic review of RCTs, or RCT rated as 1⁺⁺ and directly applicable to the target population; or
A	A body of evidence consisting principally of studies rated as 1⁺, directly applicable to the target population, and demonstrating overall consistency of results
B	A body of evidence including studies rated as 2⁺⁺, directly applicable to the target population, and demonstrating overall consistency of results; or
B	Extrapolated evidence from studies rated as 1⁺⁺ or 1⁺
C	A body of evidence including studies rated as 2⁺, directly applicable to the target population and demonstrating overall consistency of results; or
C	Extrapolated evidence from studies rated as 2⁺⁺
D	Evidence level 3 or 4; or
D	Extrapolated evidence from studies rated as 2⁺
Good practice point (GPP)	Recommended best practice based on the clinical experience of the guideline development group.

Table 2

Assessment and investigation of acute stroke and transient ischemic attack

A	A full medical assessment should be undertaken and multidisciplinary assessment considered for all patients with acute stroke or transient ischemic attack (TIA) to define the nature of the event, the need for investigations, further management and rehabilitation.
Grade A, Level 1++
C	A swallowing assessment should be undertaken at home or in hospital as part of the clinical assessment of stroke.
Grade C, Level 2+
GPP	Local written protocols should be available for healthcare institutions, setting out indications for both routine and more specialized investigations.
GPP
C&GPP	All patients with transient ischemic attack or an acute stroke syndrome should have a computed tomography or magnetic resonance imaging brain scan as soon as possible*, preferably within 24 h†.

Grade C, Level 2+

†

GPP

Table 3

Immediate management following acute stroke

A	Intravenous recombinant tissue plasminogen activator is recommended for ischemic stroke patients within three-hours of stroke onset and without contraindication to this therapy, in centers with appropriate facilities and expertise.
Grade A, Level 1+
A	Intra-arterial thrombolysis is an option for treatment in selected patients within six-hours of onset of major middle cerebral artery infarction, who are otherwise not eligible for intravenous thrombolysis.
Grade A, Level 1+
A	The routine use of heparins in acute ischemic stroke, including cardioembolic strokes, is not recommended.
Grade A, Level 1+
A	Antiplatelet therapy, normally aspirin, should be prescribed immediately for patients who have sustained an ischemic stroke.
Grade A, Level 1+
A	Early decompressive surgery is an option for treatment in patients aged between 18–60 years, with a space-occupying middle cerebral artery infarction.
Grade A, Level 1++
A	The routine use of drugs to limit neural damage, including the use of corticosteroids, neuroprotectants, plasma volume expanders, barbiturates, and streptokinase, is of no proven benefit and should be discouraged.
Grade A, Level 1+
GPP	Mild and moderately elevated blood pressure should not routinely be lowered in the acute phase of stroke as this may worsen outcome.
GPP
GPP	Patients with hemorrhagic strokes who are receiving anticoagulants or have received recent thrombolytic therapy or those with bleeding diastheses require urgent correction of coagulation defects. Thrombolytics, antiplatelet therapy and anticoagulants should be discontinued.
GPP
D	Urgent neurosurgical assessment should be available for selected patients, such as those with large cerebellar infarcts or hemorrhage or acute hydrocephalus, and for selected cases of cerebral hemorrhage.
Grade D, Level 4
GPP	Monitoring and management of hyperglycaemia is recommended for all patients with acute ischemic stroke.
GPP
B	If glucose lowering therapy is initiated, close monitoring of glucose concentrations to avoid hypoglycaemia is recommended.
Grade B, Level 1+
GPP	Hypoglycaemia in patients with acute ischemic stroke should be treated with a goal to achieve normoglycaemia.
GPP
D	When fever occurs in patients with acute ischemic stroke, the temperature should be lowered and the cause ascertained and treated.
Grade D, Level 4
D	Good hydration and early mobilisation is recommended for all stroke patients to reduce deep venous thrombosis and pulmonary embolism.
Grade D, Level 2+
A	Antiplatelet therapy is recommended in all patients with ischemic stroke to reduce deep venous thrombosis and pulmonary embolism.
Grade A, Level 1+

Table 4

Secondary prevention following acute ischemic stroke and transient ischemic attack

A	Antiplatelet therapy should be continued in the long term for the secondary prevention of recurrent stroke and other vascular events in patients who have sustained an ischemic cerebrovascular event.
Grade A, Level 1++
A	Long-term anticoagulation with adjusted dose warfarin (target INR 2·5, range 2·0–3·0) is recommended in the secondary prevention of stroke following atrial fibrillation unless there are contraindications.
Grade A, Level 1++
A	In patients with cardioembolic strokes and definite contraindications to long term anticoagulation, antiplatelet therapy should be considered.
Grade A, Level 1++
A	Patients with moderate or severe internal carotid artery stenosis ipsilateral to a carotid transient ischemic attack (TIA) or nondisabling ischemic stroke should be considered for carotid endarterectomy by an experienced surgeon.
Grade A, Level 1++
A	Carotid artery stenting may be considered in patients who are not suitable for carotid endarterectomy.
Grade A, Level 1++
C	Intracranial angioplasty with or without stenting may be considered as a treatment option for symptomatic patients who have >50% stenosis and who have failed medical therapy.
Grade C, Level 2+
A	Blood pressure lowering should be considered after the acute phase of stroke.
Grade A, Level 1++
A	Patients with ischemic stroke or TIA are reasonable candidates for treatment with a statin agent to reduce the risk of vascular outcomes. However, caution should be exercised for patients with hemorrhagic stroke.
Grade A, Level 1++
A&B	Glucose control is recommended to near normoglycaemic levels among diabetics with ischemic stroke or transient ischemic attack to reduce microvascular complications* and possibly macrovascular complications†.
*Grade A, Level 1+
†Grade B, Level 2++
D&GPP	Smoking cessation, limited alcohol consumption, weight control, regular physical activity, and a diet rich in fruits, vegetables, fish oil, and low fat dairy products may be beneficial for reducing the risk of ischemic stroke and TIA.
Grade D, Level 4
GPP

Table 5

Rehabilitation

A	Stroke patients should receive organized inpatient multidisciplinary rehabilitation.
Grade A, Level 1+
B	Stroke patients should receive early rehabilitation.
Grade B, Level 2++
A	If able to do so, stroke patients should be encouraged to participate in more intensive rehabilitation particularly in the first six-months.
Grade A, Level 1+
A	Stroke rehabilitation should include physiotherapy and occupational therapy.
Grade A, Level 1+
A	Dysphagia therapy is recommended for all acute stroke patients with impaired swallowing function.
Grade A, Level 1+
D	Speech and language therapy may be considered for poststroke communication disorder but there is presently no clear evidence for its efficacy.
Grade D, Level 3
A	Constraint-induced movement therapy is recommended for patients with upper limb paralysis who are able to tolerate the treatment regime.
Grade A, Level 1+
C	Body weight support treadmill ambulation or acupuncture may be considered but there is presently no clear evidence for its efficacy.
Grade C, Level 2+

Table 6

Implications for service delivery

A	Patients with transient ischaemic attack (TIA) or minor stroke should be referred for urgent assessment in specialized clinics.
Grade A, Level 1+
A	Patients who have suffered an acute stroke should be admitted to a stroke unit.
Grade A, Level 1++
A	Acute inpatient care for patients admitted to hospital with a stroke should be organized as a multidisciplinary stroke service based in designated stroke units.
Grade A, Level 1⁺⁺

The complete version of the guidelines is available at http://www.moh.gov.sg/mohcorp/publications.aspx?id=22920

Objectives of the guidelines

The primary aim of these guidelines is to assist individual clinicians, hospital departments, and hospital administrators in producing local protocols for:

assessment, investigation, and immediate management of individuals with a TIA or acute stroke (other than sub-arachnoid hemorrhage), and

secondary prevention and risk factor management following a TIA or acute stroke

The secondary aim of these guidelines is to suggest methods for implementation and clinical audit.

Development process of the guidelines

The workgroup, formed by the Ministry of Health, Singapore, comprised specialists from neurology, neurosurgery, neuroradiology, rehabilitation, family medicine, nursing, occupational therapy, and a lay patient advocate. The Scottish Intercollegiate Guidelines Network's Clinical Practice Guidelines on the Management of Patients with Stroke (4) were reviewed, updated and modified to meet local needs. The system of levels of evidence and grades of recommendation used to grade recommendations are shown in Table 1. The draft guidelines were then sent to various professional organizations for comments and endorsements. The final version was sent to all medical practitioners in Singapore, and also made available on the website of the Ministry of Health. The guidelines will form the basis of the ministry's audit of clinical practice by healthcare organizations.

Summary of evidence

Assessment and investigation of acute stroke and TIA is given in Table 2.

Multidisciplinary assessment, as part of the organized stroke unit care, involving nursing and other medical professionals, should begin as soon as possible in the management of a patient with a stroke (5). Assessment of swallowing should be undertaken before permitting oral intake. Nurses may be trained to perform an initial dysphagia screen. Patients with swallowing defects should be referred to a speech therapist.

Neuroimaging by computed tomography (CT) or magnetic resonance imaging (MRI) is essential for accurate diagnosis (6). Both allow a definitive diagnosis, differentiation of ischemic from hemorrhagic stroke, exclusion of mimics, and assessment of arterial and venous flow and brain perfusion (7, 8).

Other imaging modalities include carotid ultrasound, transcranial Doppler ultrasound and digital subtraction angiography.

Immediate management following acute stroke is shown in Table 3.

Cerebral infarct

Intravenous recombinant tissue plasminogen activator (rtPA) significantly improves functional outcome at three-months and one-year in patients treated within three-hours of ischemic stroke onset (9, 10). Although it carries the risk of symptomatic brain hemorrhage with high mortality, it is safe and effective in routine clinical practice (11).

Intravenous rtPA therapy commenced between 3–4·5 h after stroke onset is also associated with significantly increased favorable outcomes (12), but the benefit is less than rtPA initiated within three-hours. Thus intravenous rtPA should be initiated as soon as possible in suitable patients within three-hours of stroke onset, with possible extension of the treatment time window to 4·5 h.

Intra-arterial prourokinase in patients with stroke in the middle cerebral artery (MCA) territory of less than six-hours duration gives better clinical outcomes vs. placebo despite a slightly higher rate of hemorrhage (13).

Thrombolysis requires the patient to be at an experienced stroke center with immediate access to cerebral angiography and qualified interventionalists.

Mechanical devices (MERCI, Concentric Medical Inc, Mountain View, California, USA) may be effective in clot retrieval, while ultrasound-enhanced thrombolysis may improve recanalization, but improved clinical outcome has not yet been demonstrated (14–16).

Heparins (unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or heparinoids) do not reduce mortality. Any reduction in recurrent stroke is offset by the increase in symptomatic intracranial hemorrhage (17).

Commencement of aspirin within 48 h of ischemic stroke onset reduces early recurrence (18, 19).

Decompressive surgery improves functional outcome and reduces mortality when undertaken within 48 h of stroke onset in patients aged between 18 and 60 years, with a space-occupying MCA-territory infarction (20).

Corticosteroids, hemodilution, and neuroprotectants confer no benefit (20–24).

Blood pressure

A reduction of blood pressure occurring as a side effect of treatment is associated with a worsening of outcome (25).

The current recommendation is to carefully treat hypertension if SBP>220 mmHg or DBP>120 mmHg. Exceptions include patients who have been thrombolysed, have hypertensive encephalopathy, aortic dissection, acute renal failure, acute myocardial infarction, or acute pulmonary edema (26). Conversely, persistent hypotension should be corrected speedily (26).

Neurosurgical intervention

Early surgical evacuation of spontaneous, supratentorial, intraparenchymal hematomas is not better than conservative treatment (27). Surgical evacuation of intraparenchymal hematomas could be considered if the hematoma is thought to be causing clinical deterioration.

Ventricular shunting and decompression surgery should be considered in patients with cerebellar stroke and acute hydrocephalus due to compression of the aqueduct of Sylvius (28).

Medical management

Hyperglycemia

There is no benefit of maintaining normoglycemia by glucose–potassium–insulin infusion (29); if glucose lowering therapy is initiated during acute stroke, close monitoring of glucose concentrations to avoid hypoglycemia is needed.

Hypoglycemia

Hypoglycemia should be treated. The goal is to achieve normoglycaemia. Marked elevation of blood glucose levels should be avoided.

Fever

Paracetamol is modestly effective in lowering temperature in acute stroke (30).

Venous thromboembolism

Thigh-length, graduated compression stockings result in a non-significant, absolute reduction in deep vein thrombiosis (DVT) but lead to significantly more skin breaks, ulcers, blisters, and skin necrosis (31). Mechanical compression devices are effective in aneurysm patients (32).

In acute ischemic stroke, aspirin reduces DVT and pulmonary embolism (PE) (33, 34).

Heparin reduces the risk of asymptomatic DVT (35, 36). However, the small non-significant reduction in PE is more than offset by an increase in intracranial and extracranial hemorrhage (34). LMWH may be safer than sub-cutaneous UFH. Other measures that may prevent DVT include early mobilization, and good hydration (36).

Secondary prevention (Table 4)

Antiplatelet therapy

Long-term antiplatelet therapy reduces the risk of serious vascular events (recurrent stroke, myocardial infarction, or vascular death) following an ischemic stroke or TIA (37).

Aspirin was the most widely studied antiplatelet drug, with doses of 75–150 mg/day being at least as effective as higher daily doses. The effects of doses lower than 75 mg/day were less certain (37).

Other beneficial antiplatelet agents include ticlopidine, clopidogrel, and dipyridamole (alone or in combination with aspirin) (37). Clopidogrel or the combination of aspirin and dipyridamole may be superior to aspirin alone (37, 38).

The combination of aspirin and clopidogrel is not superior to aspirin or clopidogrel alone (39, 40).

Anticoagulation therapy

Long-term anticoagulation with adjusted dose warfarin (target INR 2.5, range 2·0–3·0) is indicated for secondary prevention if atrial fibrillation is present, unless there are contraindications (41). A lower target INR of 2·0 (range 1·6–2·5) may be preferred in frail elderly (>75 years old) patients or who have an increased risk of hemorrhagic complications (41). In patients with definite contraindications to long-term anticoagulation, antiplatelet therapy should be considered (41, 42).

Carotid endarterectomy (CEA)

When combined with aspirin, CEA reduces recurrence risk, compared to taking aspirin alone, in patients with 70–99% North American Symptomatic Carotid Endarterectomy Trial (NASCET)-measured internal carotid stenosis ipsilateral to a carotid territory TIA or nondisabling ischemic stroke (43). CEA may also benefit selected high-risk patients with symptomatic 50–69% (NASCET-measured) stenosis. The benefit is generalizable only to surgically-fit patients operated on by surgeons with acceptable complication rates.

Carotid artery stenting (CAS)

There is still controversy as to whether CAS is as effective as CEA for secondary prevention in patients with severe carotid artery stenosis (44–47). CAS is reasonable when performed with operative morbidity and mortality rates of 4–6%, similar to that observed in trials of CEA.

Intracranial angioplasty and stenting

Patients presenting with severe intracranial stenosis experience an ipsilateral stroke despite treatment with either warfarin or aspirin (48).

Intracranial stents are deployable successfully, with an acceptable procedural death and ipsilateral stroke rates (49–51).

Blood pressure lowering

While aggressive lowering of mild to moderate elevated blood pressure is not recommended during the acute phase, subsequent blood pressure reduction results in a further reduction of vascular events (52, 53). The benefit is seen in both ischemic and hemorrhagic stroke, in both hypertensive and nonhypertensive subjects (53).

Lipids

Statins reduce vascular events among patients with stroke or TIA (54, 55).

Diabetes

There are no dedicated secondary prevention trials focusing on antidiabetic therapy; hypoglycaemic agents (in particular, metformin in over-weight subjects) are helpful in prevention (56). Hence, glucose control is recommended to near normoglycaemic levels among diabetics with ischemic stroke or TIA to reduce microvascular complications and possibly macrovascular complications (57).

Lifestyle modification

Diet rich in fruits, vegetables, fish oil, and low fat dairy products may be beneficial for reducing ischemic stroke or TIA risk (58, 59).

Elevated stroke risk due to smoking declines after quitting and is eliminated after five-years (60). Smoking cessation is recommended for patients with stroke or TIA.

Drinking one to two drinks per day appears to reduce risk of ischemic stroke, while heavy drinking increases the risk (61). Patients with stroke or TIA who are heavy drinkers should eliminate or reduce alcohol consumption.

Obesity is associated with stroke susceptibility (62). Patients who are overweight with ischemic stroke and TIA should attempt weight reduction.

Increased physical activity is protective against stroke (63). Patients who are capable of exercise after stroke or TIA should maintain moderate intensity physical exercise most days of the week for at least 30 min.

Rehabilitation (Table 5)

Organized inpatient multidisciplinary rehabilitation is associated with reduced odds of death, institutionalization and dependency (64).

Patients with acute stroke benefit from early initiation of stroke rehabilitation, with better functional outcome and shorter length of stay (65–67).

More intensive and longer rehabilitation therapy during the first six-months poststroke has a small but favorable effect on functional outcome (67, 68).

In-hospital care pathways result in no significant differences in death, dependency, or discharge destination. Care pathway patients are less likely to suffer urinary tract infection or be readmitted to hospital, and are more likely to have CT brain or carotid duplex scans. However, patient satisfaction and quality of life may be significantly lower, with no significant difference in length of stay (69).

A mixed physiotherapy approach for promoting postural control and lower limb function is significantly more effective than no treatment at improving functional independence (70).

Occupational therapy interventions reduces odds of a poor outcome, and increases activity of daily living (ADL) scores – patients are less likely to deteriorate and more likely to be independent in ADLs (71).

Dysphagic patients with dietary modification and taught swallowing compensation strategies have increased return to normal diet and recovery of swallowing by six-months, especially with a high-intensity program (72).

The efficacy of formal speech and language therapy on poststroke communication disorders including aphasia, speech apraxia, and dysarthria have not been clearly determined (73–75).

There may be substantial and long-lasting improvement in functional use of the paretic upper limb with constraint-induced movement therapy (76, 77).

There are no statistically significant differences between treadmill training, with or without body weight support, and other interventions for walking speed or dependence. Subjects who could walk independently at the start of treatment tend to have higher walking speeds, and dependent walkers tend to do better with treadmill training using body weight support (78).

A systematic review of randomized unconfounded clinical trials in sub-acute and chronic stroke subjects comparing acupuncture needling with placebo, sham, or no acupuncture found no trials with adequate methodological quality (79).

Implications for service delivery (Table 6)

Stroke assessment clinics

Stroke clinics facilitate the outpatient evaluation of suspected stroke/TIA patients, as well as the follow-up of stroke patients. Early initiation of existing treatments is associated with a reduction in the risk of early recurrence (80). Use of TIA clinics with 24 h access and immediate initiation of preventive treatment might reduce length of hospital stay and stroke risk (81).

Admission policies

Compared with general medical units, the management of stroke patients in a stroke unit reduces death, death or disability, and death or institutionalization. More patients are discharged home and remain at home (5). Benefits occur by reducing death from secondary complications and reducing the need for institutional care through a reduction in disability (82).

In the majority of these trials, care was provided in a designated area or ward, as opposed to a roving stroke care team. Members of the multidisciplinary team could include nurses, physiotherapists, occupational therapists, speech therapists, dieticians, medical social workers, case managers, and patient educators.

Organization of care for patients

Systems of care, including primordial and primary prevention, community education, notification and response of emergency medical services, acute treatment, sub-acute treatment and secondary prevention, rehabilitation, and continuous quality improvement activities must be established (83).

Important components of primary stroke centers are acute stroke team, written care protocols, emergency medical services, emergency department, stroke unit, neurosurgical service, commitment and support of medical organization, neuroimaging services, laboratory services, outcome and quality assessment activities, and continuing medical education (84). Comprehensive stroke centers should integrate expert health care personnel, advanced neuroimaging capabilities, surgical and endovascular techniques, and other specific infrastructure and programmatic elements such as an intensive care unit and a stroke registry (85).

Clinical quality improvement

The following clinical quality improvement parameters, based on the recommendations in this guideline, are proposed:

Proportion of stroke patients admitted to the stroke unit

Proportion of stroke patients undergoing CT or MRI head within 24 h of admission

Proportion of stroke patients undergoing screening for swallowing disorders

Proportion of patients with noncardioembolic stroke started on antiplatelet medication at discharge

Proportion of stroke patients with atrial fibrillation started on anticoagulation at discharge

Proportion of stroke patients with hyperlipidemia started on statin therapy at discharge

Proportion of eligible stroke patients receiving intravenous rtPA therapy

Proportion of patients screened for need of inpatient multidisciplinary stroke rehabilitation

Proportion of patients with TIA or minor stroke presenting to outpatient clinics who are referred for urgent assessment in specialized clinics or emergency departments.

Footnotes

Appendix

Workgroup and guideline development members: CoChairmen: Christopher Chen Li-Hsian, Lee Sze Haur.

Members: Bernard Chan, N. Venketasubramanian Ramani, Lee Kim En, Tang Kok Foo, John Thomas, Ivan Ng, Sitoh Yih Yian, Winston Lim, Lim Su Chi, Matthew Ng, Teo Wee Siong, Peter Lim Ai Chi, Winnie Tang, Ann Yin, Christopher Kuah.

Subsidiary editors: Pwee Keng Ho, Celeste Ong.

References

1 Venketasubramanian

Chen

. Burden of stroke in Singapore. Int J Stroke 2008; 3:51–4.

2 Venketasubramanian

Sadasivan

Tan

AKY

. Stroke patterns in a Singapore hospital-based stroke data bank. Cerebrovasc Dis 1994; 4:250.

3 Ministry of Health Singapore. Available at http://www.moh.gov.sg/mohcorp/hcsystem.aspx?id=102 (accessed August 15, 2010).

4 Scottish Intercollegiate Guidelines Network (SIGN). Clinical Practice Guidelines on the Management of Patients with Stroke: Assessment, Investigation, Immediate Management and Secondary Prevention. Scottish Intercollegiate Guidelines Network (SIGN), 1997

5 Stroke Unit Trialists' Collaboration. Organised inpatient (stroke unit) care for stroke (Review). The Cochrane Library 2007, Issue 3, CD000197.

6 Mohr

Biller

Hilal

. Magnetic resonance versus computed tomographic imaging in acute stroke. Stroke 1995; 26:807–12.

7 Fiebach

Schellinger

Jansen

. CT and diffusion-weighted MR imaging in randomized order: diffusion-weighted imaging results in higher accuracy and lower interrater variability in the diagnosis of hyperacute ischemic stroke. Stroke 2002; 33:2206–10.

8 Esteban

Cervera

. Perfusion CT and angio CT in the assessment of acute stroke. Neuroradiology 2004; 46:705–15.

9 National Institute of Neurological Disorders and Stroke rt-PA Study Group. Tissue plasminogen activator for the treatment of acute ischaemic stroke. New Engl J Med 1995; 333:1581–7.

10.

10 Kwiatkowski

Libman

Frankel

. National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke Study Group. Effects of tissue plasminogen activator for acute ischemic stroke at one year. N Engl J Med 1999; 340:1781–7.

11.

11 Wahlgren

Ahmed

, SITS-MOST investigators et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet 2007; 369:275–82.

12.

12 Hacke

, Kaste M, for the ECASS Investigators et al. Thrombolysis with Alteplase 3 to 4·5 Hours after Acute Ischemic Stroke. N Engl J Med 2008; 359:1317–29.

13.

13 Furlan

Higashida

Wechsler

. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA 1999; 282:2003–11.

14.

14 Flint

Duckwiler

Budzik

Liebeskind

, Smith WS, for the Merci and Multi Merci Writing Committee. Mechanical thrombectomy of intracranial internal carotid occlusion: Pooled results of the MERCI and multi MERCI part I trials. Stroke 2007; 38:1274–80.

15.

15 Smith

Sung

, Multi MERCI investigators et al. Mechanical thrombectomy for acute ischemic stroke. Final results of the multi MERCI trial. Stroke 2008; 39:1205–12.

16.

16 Alexandrov

Molina

, CLOTBUST Investigators et al. Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med 2004; 351:2170–8.

17.

17 Gubitz

Sandercock

Counsell

. Anticoagulants for acute ischaemic stroke. Cochrane Database Syst Rev 2004: CD000024.

18.

18 International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet 1997; 349:1569–81.

19.

19 Chinese Acute Stroke Trial (CAST) Collaborative Group. A randomised placebo-controlled trial of early aspirin use in 20 000 patients with acute ischaemic stroke. Lancet 1997; 349:1641–9.

20.

20 Vahedi

, Hofmeijer J, for the DECIMAL, DESTINY, and HAMLET investigators et al. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol 2007; 6:215–22.

21.

21 Norris

Hachinski

. High dose steroid treatment in cerebral infarction. BMJ 1986; 292:21–3.

22.

22 Poungvarin

Bhoopat

Viriyavejakui

Rodprasert

Buranasiri

Sukhondabant

. Effects of dexamethasone in primary supratentorial intracerebral haemorrhage. N Eng J Med 1987; 316:1229–33.

23.

23 Asplund

Israelsson

Schampi

. Haemodilution for acute ischaemic stroke. Cochrane Database Syst Rev 2000: CD000103.

24.

24 Liebeskind

Kasner

. Neuroprotection for ischaemic stroke: an unattainable goal? CNS Drugs 2001; 15:165–74.

25.

25 The Blood Pressure in Acute Stroke Collaboration (BASC). Vasoactive drugs for acute stroke (Cochrane Review). In: The Cochrane Library, Issue 1, 2003. Oxford: Update Software

26.

26 Adams

Jr del Zoppo

Alberts

. Guidelines for the early management of adults with ischemic stroke: a guideline from the American heart association/American stroke association stroke council, clinical cardiology council, cardiovascular radiology and intervention council, and the atherosclerotic peripheral vascular disease and quality of care outcomes in research interdisciplinary working groups. Stroke 2007; 38:1655–711.

27.

27 Mendelow

Gregson

Fernandes

. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet 2005; 365:387–97.

28.

28 Ojemann

Heros

. Spontaneous brain haemorrhage. Stroke 1983; 14:468–74.

29.

29 Gray

Hildreth

Sandercock

. Glucose–potassium–insulin infusions in the management of post-stroke hyperglycaemia: the UK Glucose Insulin in Stroke Trial (GIST-UK). Lancet Neurol 2007; 6:397–406.

30.

30 Dippel

DWJ

van Breda

van der Worp

. Effect of paracetamol (acetaminophen) and ibuprofen on body temperature in acute ischemic stroke PAIS, a phase II double-blind, randomized, placebo-controlled trial. BMC Cardiovasc Disord 2003; 3:2.

31.

31 The CLOTS Trials Collaboration. Effectiveness of thigh-length graduated compression stockings to reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a multicentre, randomised controlled trial. Lancet 2009; 373:1958–65.

32.

32 Black

Crowell

Abbott

. External pneumatic calf compression reduces deep venous thrombosis in patients with ruptured intracranial aneurysms. Neurosurgery 1986; 18:25–8.

33.

33 Pulmonary Embolism Prevention (PEP) Trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low-dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000; 355:1295–302.

34.

34 Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy, III: reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. BMJ 1994; 308:235–46.

35.

35 Bath

PMW

Iddenden

Bath

. Low molecular weight heparins and heparinoids in acute ischaemic stroke: a systematic review. Stroke 2000; 31:311–4.

36.

36 André

de Freitas

Fukujima

. Prevention of deep venous thrombosis and pulmonary embolism following stroke: a systematic review of published articles. Eur J Neurol 2007; 14:21–32.

37.

37 Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324:71–86.

38.

38 The ESPRIT Study Group. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006; 367:1665–73.

39.

39 Diener

, Bogousslavsky J, for the MATCH Investigators et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004; 364: 331–7.

40.

40 Bhatt

, Fox KAA, for the CHARISMA Investigators et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354:1706–17.

41.

41 EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 1993; 342:1255–62.

42.

42 Hylek

Singer

. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120:897–902.

43.

43 Rothwell

Elaiswiz

Gutriknov

. Analysis of pooled data from the randomised controlled trials of endarterectomy for symptomatic carotid stenosis. Lancet 2003; 361:107–16.

44.

44 Kastrup

Groschel

. Carotid endarterectomy versus carotid stenting: an updated review of randomized trials and subgroup analyses. Acta Chir Belg 2007; 107:119–28.

45.

45 Eckstein

Ringleb

Allenberg

. Results of the Stent-Protected Angioplasty versus Carotid Endarterectomy (SPACE) study to treat symptomatic stenoses at 2 years: a multinational, prospective, randomised trial. Lancet Neurol 2008; 7:893–902.

46.

46 Mas

Trinquart

, EVA-3S investigators et al. Endarterectomy Versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial: results up to 4 years from a randomised, multicentre trial. Lancet Neurol 2008; 7:885–92.

47.

47 Gurm

, Yadav JS, for the SAPPHIRE investigators et al. Long-term results of carotid stenting versus endarterectomy in high-risk patients. N Engl J Med 2008; 358:1572–9.

48.

48 Chimowitz

Kokkinos

Strong

. The warfarin–aspirin symptomatic intracranial disease study. Neurology 1995; 45:1488–93.

49.

49 SSYLVIA Study Investigators. Stenting of Symptomatic Atherosclerotic Lesion in the Vertebral or Intracranial Arteries (SSYLVIA): Study results. Stroke 2004; 35:1388–92.

50.

50 Bose

Hartmann

Henkes

. A novel, self-expanding, nitinol stent in medically refractory intracranial atherosclerotic stenoses the wingspan study. Stroke 2007; 38:1531–7.

51.

51 Fiorella

Levy

Turk

. US multicenter experience with the wingspan stent system for the treatment of intracranial atheromatous disease periprocedural results. Stroke 2007; 38:881–7.

52.

52 Rashid

Leonardi-Bee

Bath

. Blood pressure reduction and secondary prevention of stroke and other vascular events: a systematic review. Stroke 2003; 34:2741–8.

53.

53 PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358:1033–41.

54.

54 Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20 536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004; 363:757–67.

55.

55 Amarenco

Bogousslavsky

Callahan

III . High dose atorvastatin after stroke or transient ischemic attack (SPARCL). N Engl J Med 2006; 355:549–59.

56.

56 UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352:854–65.

57.

57 The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353:2643–53.

58.

58 He

Nowson

MacGregor

. Fruit and vegetable consumption and stroke: meta-analysis of cohort studies. Lancet 2006; 367:320–6.

59.

59 He

Song

Daviglus

. Fish consumption and incidence of stroke: a meta-analysis of cohort studies. Stroke 2004; 35:1538–42.

60.

60 Wannamethee

Shaper

Whincup

Walker

. Smoking cessation and the risk of stroke in middle-aged men. JAMA 1995; 274:155–60.

61.

61 Reynolds

Lewis

Nolen

Kinney

Sathya

. Alcohol consumption and risk of stroke: a meta-analysis. JAMA 2003; 289:579–88.

62.

62 Wilson

D'Agostino

Sullivan

Parise

Kannel

. Overweight and obesity as determinants of cardiovascular risk: the Framingham experience. Arch Intern Med 2002; 162:1867–72.

63.

63 Wendel-Vos

Schuit

Feskens

. Physical activity and stroke. A meta-analysis of observational data. Int J Epidemiol 2004; 33:787–98.

64.

64 Langhorne

Duncan

. Does the organization of postacute stroke care really matter? Stroke 2001; 32:268–74.

65.

65 Maulden

Gassaway

Horn

Smout

DeJong

. Timing of initiation of rehabilitation after stroke. Arch Phys Med Rehabil 2005; 86(Suppl. 2): S34–40.

66.

66 Salter

Jutai

Hartley

. Impact of early versus delayed admission to rehabilitation on functional outcomes in persons with stroke. J Rehabil Med 2006; 38:113–7.

67.

67 Horn

DeJong

Smout

. Stroke rehabilitation patients, practice, and outcomes: Is earlier and more aggressive therapy better? Arch Phys Med Rehabil 2005; 86(Suppl. 2): S101–14.

68.

68 Kwakkel

va Peppen

Wagenaar

. Effects of augmented exercise therapy time after stroke: a meta-analysis. Stroke 2004; 35:2529–36.

69.

69 Kwan

Sandercock

. In-hospital care pathways for stroke: a Cochrane systematic review. Stroke 2003; 34:587–8.

70.

70 Pollock

Baer

Langhorne

Pomeroy

. Physiotherapy treatment approaches for the recovery of postural control and lower limb function following stroke: a systematic review. Clin Rehabil 2007; 21:395–410.

71.

71 Legg

Drummond

Langhorne

. Occupational therapy for patients with problems in activities of daily living after stroke. Cochrane Database Syst Rev 2006: CD003585.

72.

72 Carnaby

Hankey

Pizzi

. Behavioural intervention for dysphagia in acute stroke: a randomised controlled trial. Lancet Neurol 2006; 5:31–7.

73.

73 Greener

Enderby

Whurr

. Speech and language therapy for aphasia following stroke. Cochrane Database Syst Rev 2000: CD000425.

74.

74 West

Hesketh

Bowen

. Interventions for apraxia of speech following stroke. Cochrane Database Syst Rev 2005: CD004298.

75.

75 Sellars

Hughes

Langhorne

. Speech and language therapy for dysarthria due to non-progressive brain damage. Cochrane Database Syst Rev 2005: CD002088.

76.

76 Wolf

Winstein

Miller

. Effect of constraint-induced movement therapy on upper extremity function 3 to 9 months after stroke: the EXCITE randomized clinical trial. JAMA 2006; 296:2095–104.

77.

77 Wolf

Winstein

Miller

. Retention of upper limb function in stroke survivors who have received constraint-induced movement therapy: the EXCITE randomized trial. Lancet Neurol 2008; 7:33–40.

78.

78 Mosely

Stark

Cameron

Pollock

. Treadmill training and body weight support for walking after stroke. Cochrane Database Syst Rev 2005: CD002840.

79.

79 Wu

Tang

Lin

. Acupuncture for stroke rehabilitation. Cochrane Database Syst Rev 2006: CD004131.

80.

80 Rothwell

Giles

Chandratheva

. Early use of Existing Preventive Strategies for Stroke (EXPRESS) study. Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke (EXPRESS study): a prospective population-based sequential comparison. Lancet 2007; 370:1432–42.

81.

81 Lavallée

Meseguer

Abboud

. A transient ischaemic attack clinic with round-the-clock access (SOS-TIA): feasibility and effects. Lancet Neurol 2007; 6:953–60.

82.

82 Govan

Langhorne

, Weir CJ Stroke Unit Trialists Collaboration. Does the prevention of complications explain the survival benefit of organized inpatient (stroke unit) care? Further analysis of a systematic review. Stroke 2007; 38:2536–40.

83.

83 American Stroke Association's Task Force on the Development of Stroke Systems. Recommendations for the establishment of stroke systems of care. Stroke 2005; 36:690–703.

84.

84 Brain Attack Coalition. Recommendations for the establishment of primary stroke centres. JAMA 2000; 283:3102–9.

85.

85 Brain Attack Coalition. Recommendations for comprehensive stroke centers. Stroke 2005; 36:1597–618.