Seminar

Stroke
Georey A Donnan, Marc Fisher, Malcolm Macleod, Stephen M Davis
Lancet 2008; 371: 161223
National Stroke Research
Institute, Austin Hospital,
University of Melbourne,
Melbourne, Victoria, Australia
(Prof G A Donnan MD);
Department of Neurology,
University of Massachusetts
Medical School, Worcester, MA,
USA (Prof M Fisher MD);
Department of Neurology,
Stirling Royal Inrmary,
Stirling, UK (M Macleod PhD);
and Department of Neurology
Royal Melbourne Hospital,
University of Melbourne,
Melbourne, Victoria, Australia
(Prof S M Davis MD)
Correspondence to:
Prof Georey A Donnan,
National Stroke Research
Institute, Austin Hospital,
University of Melbourne,
300 Waterdale Road, Heidelberg
Heights, Victoria, Australia 3081
[email protected]

1612

Stroke is the second most common cause of death and major cause of disability worldwide. Because of the ageing
population, the burden will increase greatly during the next 20 years, especially in developing countries. Advances
have occurred in the prevention and treatment of stroke during the past decade. For patients with acute stroke,
management in a stroke care unit, intravenous tissue plasminogen activator within 3 h or aspirin within 48 h of
stroke onset, and decompressive surgery for supratentorial malignant hemispheric cerebral infarction are interventions
of proven benet; several other interventions are being assessed. Proven secondary prevention strategies are warfarin
for patients with atrial brillation, endarterectomy for symptomatic carotid stenosis, antiplatelet agents, and
cholesterol reduction. The most important intervention is the management of patients in stroke care units because
these provide a framework within which further study might be undertaken. These advances have exposed a worldwide
shortage of stroke health-care workers, especially in developing countries.

Epidemiology
Stroke causes 9% of all deaths around the world and is
the second most common cause of death after ischaemic
heart disease.1 The proportion of deaths caused by
stroke is 1012% in western countries, and 12% of these
deaths are in people less than 65 years of age.2 In 2002,
stroke-related disability was judged to be the sixth most
common cause of reduced disability-adjusted life-years
(DALYsthe sum of life-years lost as a result of
premature death and years lived with disability adjusted
for severity).3 However, because of the burgeoning
elderly population in western societies, the estimation
is that by 2030 stroke-related disability in western
societies will be ranked as the fourth most important
cause of DALYs.4
Worldwide, stroke consumes about 24% of total
health-care costs, and in industrialised countries stroke
accounts for more than 4% of direct health-care costs.
The total costs to society have been variously estimated at
76 billion in the UK at 1995 prices, AUS$13 billion in
Australia, and US$409 billion in the USA at 1997 prices,5,6
which represents about US$100 per head of population
per year. Nevertheless, the proportion of research funds
directed towards stroke remains disproportionately and
disappointingly low.7
Although, the average age-adjusted stroke mortality for
developed countries is about 50100 per 100 000 people
per year, there are dierences between countries. For
example, projections for 2005 based on age-standardised
death rates for ages 3069 years in the Russian Federation
were greater than 180 per 100 000 people, whereas for
Canada they were less than 15 per 100 000 people (gure 1).8
Such strong geographical variations might suggest a role
for dierences in the prevalence of risk factors and genetic
factors and dierences in the management of stroke. Even
though there has been a constant reduction in stroke
mortality in developed countries during the past 50 years
(a relative reduction of about 1% per year until the
late 1960s followed by a more steep fall of as much as 5%
per year),2 we are less certain about trends in developing
countries. The most plausible explanation for the reduction
in mortality in western countries is improved control of

stroke risk factors (especially high blood pressure and

cigarette smoking) combined with a parallel improvement
in living standards.9,10 The lessons for the developing world
are obvious.
In a community-based study, the incidence of cerebrovascular events (transient ischaemic attack [TIA] and
ischaemic stroke) was higher than that of ischaemic
heart disease or peripheral vascular disease (table 1).11
Apparent dierences in reported stroke incidence might
result from methodological weaknesses in individual
studies. Even in studies of the highest quality, stroke
incidence ranges from 240 per 100 000 people in Dijon,
France (standardised to the European population aged
4584 years), to about 600 per 100 000 people in
Novosibirsk, Russia,12 again suggesting important roles
for both environmental and genetic factors. However, for
the rst time, substantial reductions in the incidence of
stroke have been reported, although less is known about
changes in stroke severity or incidence of TIAs. For
instancebetween 1989 and 1995a 25% reduction in
stroke incidence was seen in Perth, Australia, and
between 1981 and 2002a 29% reduction was seen in
Oxfordshire, UK; these reductions imply that improved
risk-factor management can have a substantial eect in
some societies (gure 2). By contrast, in Novosibirsk
between 1987 and 1994stroke incidence in people aged
3569 years actually rose. Less attention has been paid to
Search strategy and selection criteria
We searched Medline for English language manuscripts. We
used the search terms stroke prognosis, secondary
prevention, primary prevention, intracerebral
haemorrhage, and acute stroke therapies in combination
with the term review. We largely selected publications in
the past 5 years, but did not exclude commonly referenced
and highly regarded older publications. We also searched the
reference lists of articles identied by the search strategy and
selected those we judged relevant. Review articles are cited to
provide readers with details, and major studies or trials are
cited to support level 1 evidence.

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Seminar

Subtypes and pathophysiology

Strokes are either ischaemic or haemorrhagic. Because
the management of these subtypes is so dierent, the
clinical distinction between the subtypes is one of the
most important and urgent steps in stroke management.
This distinction has been revolutionised by the
introduction of CT and MRI. Although CT has been the
workhorse of stroke diagnosis during the past 20 years,
MRI is now as useful as, if not more so than, CT.15
Further systems for stroke classication have been
driven by the needs of both clinical trials (that have led to
the introduction of the Trial of Org 10172 in Acute Stroke
Treatment [TOAST] criteria; panel) and epidemiological
studies (that have led to the Oxfordshire Community
Stroke Project [OCSP] classication).1619 The TOAST
criteria identify the most probable pathophysiological
mechanism on the basis of clinical ndings and results
of investigations,16 whereas the OCSP classication relies
exclusively on clinical ndings and is therefore broadly
applicable in any number of dierent settings in which
access to investigations might be restricted.19 In view of
the rapid advances made in imaging and other
investigations, TOAST criteria and OCSP classications
will need to be updated in the near future.

Haemorrhagic stroke (intracerebral haemorrhage)

The most common mechanism is hypertensive
small-vessel disease, which causes small lipohyalinotic
aneurysms that subsequently rupture.20 Whether other
contributing factorssuch as haemorrhage into a
previous infarctionare important needs to be clearly
established.21 About two-thirds of patients with primary
www.thelancet.com Vol 371 May 10, 2008

200
Age-standardised death rate per 100 000 population

stroke prevalence (ie, the burden of patients living with

the consequences of stroke), mainly because the
identication of such individuals is a daunting task.
Typical estimates, largely drawn from knowledge of
stroke incidence and mortality, are that about 500 people
per 100 000 population live with the consequences of
stroke. Because stroke mortality is probably decreasing
more rapidly than stroke incidence, the proportion of
stroke survivors is likely to increase, which will place
increased demands on health-care and social-care
systems.
Risk factors for stroke can be broadly classied as
modiable or xed. Some modiable risk factors (such
as hypertension, diabetes, and smoking) are common
and aect health in several ways, providing opportunities
to modify risk in large numbers of people. Other risk
factors, such as atrial brillation and TIAs, are less
prevalent and more specic than the common risk factors
for stroke. Risk factors that have been identied explain
only about 60% of the attributable risk, whereas more
than 90% of ischaemic heart disease is explained by
identiable risk factors.13,14 Investigation is needed to
identify the risk factors that account for the 40% gap,
some of which might be genetic.

180
160
140
120
100
80
60
40
20
0

Russian
Nigeria
Federation

Tanzania

India

China

Pakistan

Brazil

UK

Canada

Figure 1: Age-standardised death rates from stroke per 100 000 for ages 3069 years in selected countries,
projections for 2005
Reproduced from Strong and colleagues8 with permission.
Total number* Rate (95% CI)
Cerebrovascular events
Ischaemic stroke

550

201 (185219)

41

015 (011020)

Subarachnoid haemorrhage

27

010 (007014)

Transient ischaemic attack

300

110 (098123)

All cerebrovascular events

918

336 (314358)

Sudden cardiac death

163

060 (05107)

STEMI

159

058 (049068)

N-STEMI

316

116 (103129)

Unstable angina

218

080 (070091)

All coronary vascular events

856

313 (293335)

188

069 (059079)

Intracerebral haemorrhage

Coronary vascular events

Peripheral vascular events

All events

Stroke incidence was greater than ischaemic heart disease or peripheral vascular
disease, which emphasised the need for greater resource allocation for the rst
and last event (modied from Rothwell and colleagues11 with permission).
STEMI=ST-segment elevation acute myocardial infarction.
N-STEMI=non-ST-segment elevation acute myocardial infarction. *Number of
events during 3 years. Number of events per 1000 population per year.

Table 1: The incidence of cerebrovascular, coronary, and peripheral

vascular events (rst and recurrent) in the Oxford vascular study

cerebral haemorrhage have either pre-existing or newly

diagnosed hypertension.22 The remaining patients might
be seen, on more detailed investigation, to have
intracranial vascular malformations (cavernous angiomas
or arteriovenous malformations), cerebral amyloid
angiopathy, or infarcts into which secondary haemorrhage
has occurred.
Subarachnoid haemorrhage is classied as a type of
stroke, and accounts for about 5% of all strokes. Most
subarachnoid haemorrhages are caused by rupture of
saccular aneurysms within the subarachnoid space.
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Seminar

Change (%)

30
20

+22

+17

+18

+13

10
0
10
20

12

30
40
50

25

Region

Sweden
Denmark
Estonia
USA
Soderhamm Rochester Frederiksberg Tartu

Year of study
Interval (years)

197583
8

29

New Zealand Sweden

Australia UK
Oxfordshire
Auckland
Soderhamm Perth

Ischaemic penumbra and cascade

Perimesencephalic haemorrhages are thought to be

caused by rupture of intracranial veins; they are less
severe, have a better prognosis, and generally no aneurysm
is seen on angiography.23

Once vessel occlusion has occurred, a volume of

functionally impaired, but structurally intact, tissue
surrounds the ischaemic core.29 This tissue is known as
the ischaemic penumbra and is the target for therapeutic
interventions since its salvage is associated with
neurological improvement and recovery.30 The state of
functional impairment with structural integrity has
been seen with magnetic resonance scanning in some
patients up to 24 h after stroke onset; mismatch between
the volume of brain with reduced perfusion is shown
on perfusion-weighted imaging, and the volume of
brain showing cellular swelling, the ischaemic core, is
shown on diusion weighted imaging (gure 3). The
penumbra is seen up to 48 h after stroke onset by use of
PET.31,32
Within the ischaemic penumbra, a cascade of
neurochemical events begins with energy depletion
followed by disruption of ion homoeostasis, release of
glutamate, calcium channel dysfunction, release of free
radicals, membrane disruption, inammatory changes,
and necrotic and apoptotic cell death triggering.33 In
animal models of stroke, these cascades can be arrested
at various points, which forms the basis of neuroprotective
therapies that are discussed subsequently.34 The infarct
core contains tissue that is unsalvageable and represents
the terminal events of the ischaemic cascade.

Ischaemic stroke and transient ischaemic attacks

Stroke prognosis

About 80% of all strokes are ischaemic.24 Classication

based on the OCSP system can be done in the emergency
room and conveys important prognostic information.
Classication based on the TOAST system identies the
mechanism that leads to vessel occlusion (cardioembolic,
artery to artery embolism, or in-situ small-vessel
[lacunar] disease) and is important in everyday
management because such information should
inuence both acute treatments and secondary
prevention strategies.
The distinction between symptomatic cerebral
ischaemic events that last 24 h or less (TIAs) and events
of longer duration (stroke) is entirely arbitrary. Permanent
tissue damage can be seen with MRI in at least 25% of
patients with TIAs25,26 and some have argued that a new
denition of TIAs incorporating such imaging ndings
is needed.27 We believe that the diagnosis of symptomatic
cerebral ischaemic events remains essentially clinical
and should trigger an appropriate emergency response

About a quarter of stroke patients are dead within a

month, about a third by 6 months, and a half by 1 year.35,36
Prognosis is even worse for those with intracerebral and
subarachnoid haemorrhage because the 1-month
mortality approaches 50%. The major cause of early
mortality is neurological deterioration with contributions
from other causes such as infections secondary to
aspiration (if not managed aggressively), but later deaths
are more commonly caused by cardiac disease or
complications of stroke.36 In the OCSP classication, the
1-year mortality for patients with total anterior circulation
syndromes (about 60%) is substantially higher than that
for those with partial anterior circulation and posterior
circulation syndromes (about 1520%), which in turn is
higher than that for patients with lacunar
syndromes (10%).37,38 The best predictors of stroke
recovery at 3 months are the initial neurological decit
and age; other factors include high blood glucose
concentrations, body temperature, and previous stroke.39

197580
5

197289
17

197091 198191
10
21

198387
4

198995 19812002
21
6

Figure 2: Trends in stroke incidence in eight ideal stroke incidence studies

Note that the trends in later decades are toward reductions in incidence in developed countries in which the eect
of risk factor modication may be becoming evident.

Panel: Classication of subtypes of acute ischaemic stroke

TOAST* (Trial of Org 10 172 in Acute Stroke Treatment)
criteria16
Large-artery atherosclerosis (embolus or thrombosis)*
Cardioembolism (high-risk or medium-risk)*
Small-vessel occlusion (lacune)*
Stroke of other determined cause*
Stroke of undetermined cause
Two or more causes identied
Negative evaluation
Incomplete evaluation
*Possible or probable depending on results of ancillary studies.

1614

in the community, from primary care physicians through

to those in emergency departments. Response should be
based on the clinical features of an individual case (for
instance, the ABCD score based on age [A], blood
pressure [B], clinical features [C], and duration of
symptoms [D], table 2), and the role of imaging is to
eliminate other causes and help to stratify the risk of
early recurrence.

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Seminar

Feature

Points

Age 60 years or older

Blood pressure elevation on rst assessment

(140 mm Hg systolic, 90 mm Hg diastolic)

Clinical features of transient ischaemic stroke

Unilateral weakness

Speech impairment without weakness

Duration of transient ischaemic attack

60 min

1059 min

Diabetes

DWI
A score of 4 points or more might justify admission to hospital or urgent
evaluation, treatment, and observation since 30-day stroke risk is in the order of
515%. Reproduced from Johnston and colleagues.28

Table 2: ABCD score

A third of patients with primary intracerebral

haemorrhage have a rapid expansion of the haematoma
within the rst few hours after presentation, which is an
independent predictor of poor outcome at 3 months
alongside other factors such as age and initial
neurological decit (gure 4).40
After TIA or minor stroke, the risk of further stroke is
substantially higher than previously thought, reaching as
high as 30% within the rst month in some subgroups.4144
Patients at very high risk (>30%) of recurrence within
7 days can be identied on the basis of their age, blood
pressure, and the characteristics and duration of their
symptoms; simple scores have been developed, on the
basis of these factors, to predict those patients at greatest
risk who might benet most from early risk-factor
modication (table 2).28,45 Additionally, imaging
strategiesfor instance the presence of diusionweighted image lesions on magnetic resonance scanning
or of occluded vessels on magnetic resonance
angiographycan identify patients at increased risk of
recurrence.46

Acute interventions
Stroke care units (SCUs)
Remarkable advances in the management of acute
stroke seen in the past 1015 years consist of four
proven interventions supported by level 1 evidence and
various promising interventions under investigation
(table 3). Without doubt the most substantial advance
in stroke has been the routine management of patients
in SCUs, which is eective and appropriate for all
stroke subtypes, and provides a focus for professionals
in stroke care. Management of patients within an SCU
reduces mortality by about 20% and improves functional
outcome by about the same amount.47 A physical space
identied as an SCU is associated with better outcomes
than seen with a dedicated stroke team visiting patients
on general medical wards.72 Although the precise
components of SCU management responsible for the
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PWI

Figure 3: MRI of the ischaemic penumbra

Mismatch between large perfusion decit seen on perfusion-weighted image
(PWI) and infarct core seen on small-diusion-weighted image (DWI) represents
penumbral target for therapy. DWI/PWI mismatch is increasingly being used to
identify patients who are most likely to benet from new interventions in acute
ischaemic stroke.

Figure 4:
Haematoma growth seen during 24 h from the initial presentation at 35 h
(A) to 275 h (B) in a 74-year-old man with right hemiparesis
Haematoma growth is an independent predictor of outcome and is the target
for the haemostatic therapy recombinant factor VII in phase 3 clinical trials.

eectiveness of SCUs are unclear, improved blood

pressure control, early mobilisation, and general
adherence to best practice have been identied as some
of the components.73,74 In a community-based
epidemiological study, in which all patients eligible for
possible acute stroke interventions were considered,
SCU management had the potential to prevent death or
disability for around 50 patients for every 1000 strokes,
compared with about six per 1000 with tissue
plasminogen activator (tPA) and four per 1000 with
aspirin.75 The mechanisms by which SCU management
improves outcomes are uncertain. However, evidencebased advances, such as results from the prevention of
venous thromboembolism after acute ischaemic stroke
with
low-molecular-weight
heparin
enoxaparin
(PREVAIL) trial,76 have established the superiority of
enoxaparin compared with unfractionated low-dose
heparin for prevention of deep vein thrombosis after
stroke. The widespread introduction of SCUs should be
a priority in planning health systems, especially in
developing countries with high rates of death.
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Seminar

Thrombolysis: recombinant tPA

Recombinant tPA is one of the most biologically eective
treatments for acute ischaemic stroke; the number needed
to treat to improve outcome to minimum or no neurological decit in one person is about seven or about
18 people when avoidance of death or disability is
considered (table 3).48,77 However, these numbers relate to
treatment within 3 h of stroke onset. Because of the short
therapeutic time window, the number of patients who
might receive treatment and therefore potentially benet
is small; prevention of disability is seen in only six patients
per 1000 ischaemic strokes.75 tPAalthough very eective
in reducing disabilitydoes not improve mortality.77
Indeed, most stroke centres use tPA in only about 5% of
stroke patients.78 Even in developed countries, many
hospitals treating acute stroke do not oer thrombolysis,
largely because of a worldwide shortage of physicians who
are experts in acute stroke management. In some countries,
such as the USA, reimbursement might also be an issue.

Initial or important study, year

RRR (95% CI)

ARR

NNT1

Acute stroke
Proven
Stroke unit47

Langhorne and colleagues, 1993

65%

38%

Thrombolysis (tPA)48

NINDS, 1995

98%

55%

18

Aspirin49

IST, 1997

26%

12%

83

Decompressive surgery for IS50 Vahedi and colleagues, 2007

488%

26

23%

4*

Under investigation
Recombinant factor VII ICH51

Mayer and colleagues, 2005

Surgery for ICH52

Mendelow and colleagues, 200585

Extending time window for

thrombolysis53

DIAS, 2005

Sonothrombolysis54

Alexandrov and colleagues, 2004

Thrombectomy55

MERCI, 2005

Blood pressure lowering56

ENOS, 2007

Neuroprotection57

SAINT, 2006

Secondary prevention
Proven
Aspirin58

Canadian Co-op Study Group, 1978

130%

10%

Aspirin plus dipyridamole59

Diener, 1996

150%

19%

53

Clopidogrel60

CAPRIE, 1996

100%

16%

62

Anticoagulants61

EAFT, 1993

660%

80%

11

Carotid endarterectomy62,63

NASCET, 1991, ECST 1991

440%

38%

26

Blood pressure lowering64

PROGRESS, 2001

280%

40%

97

Cholesterol lowering65

SPARCL, 2006

160%

22%

220

100

Under investigation
Angioplasty66

Yadavand colleagues, 2004

Thrombin inhibitors67

SPORTIF, 2003

The number needed to treat (NNT1) to prevent one stroke patient dying or becoming dependent (acute stroke) or to
prevent one fatal or non-fatal stroke (secondary prevention) per year is given. All values are approximate and derived
from previous analyses, Cochrane database, or individual trials if these are the only data available.6871 RRR=relative risk
reduction. ARR=absolute risk reduction. tPA=tissue plasminogen activator. IS=ischaemic stroke. ICH=intracerebral
haemorrhage. *NNT for survival with modied Rankin scale 3. Calculations based on mean follow-up of 39 years in
PROGRESS (NNT39=25) and median 49 years in SPARCL (NNT49=45).

Table 3: Acute interventions and secondary prevention strategies of proven benet based on level I evidence

1616

The major adverse eect of thrombolysis is

symptomatic intracerebral haemorrhage, seen in
about 67% of cases. This value was somewhat lower in
a Europe-wide registry (SITS-MOST), although the
denition of symptomatic haemorrhage diered from
that in the original trials.79 Risk of symptomatic
intracerebral haemorrhage increases with age, high
blood pressure, very severe neurological decits, severe
hyperglycaemia, and, possibly, with early ischaemic
changes on CT.80,81 Data supporting an increased risk of
haemorrhage with early ischaemic change on CT come
largely from trials of therapy initiated up to 6 h after
symptom onset, and therefore might not be relevant to
therapy initiated within a 3 h time window.82 However,
most, but not all, physicians regard CT evidence of early
ischaemic change that aects more than a third of
middle-cerebral-arterial territory as a contraindication
to therapy.83 One phase III trial suggested that
prourokinase given intra-arterially within 6 h of
symptom onset can improve outcome, and various
centres routinely use this approach with results similar
to those from trials of intravenously administered tPA
(although not approved by the US Food and Drug
Administration [FDA]).84,85
Because of the substantial eectiveness of tPA, eorts
to increase the number of patients who are eligible for
thrombolytic therapy are underway. First, some
eectiveness of tPA is likely to remain beyond 3 h, and
this theory is being tested in the European cooperative
acute stroke III (ECASS III) trial and the international
stroke trial 3 (IST3).86,87 The alteplase thrombolysis for
acute noninterventional therapy in ischaemic stroke
(ATLANTIS) study, which was done before ECASS III
and IST3 studies, did not show benet in the 35 h
time window.88 Second, stroke-to-hospital times are
reduced by identication of factors associated with
delay, such as failure to immediately call an ambulance.89
Third, door-to-needle times are reduced by the use of
ecient triage pathways.90 Finally, eorts are being
made to extend the time window for therapy in
individual patients by detection of persistent ischaemic
penumbra, for instance, by use of MRI.9193

Aspirin
Evidence from about 40 000 randomised patients shows
that the administration of oral aspirin within 48 h of
onset of ischaemic stroke reduces 14-day morbidity and
mortality.49,94 However, the benet is quite small, with
only about nine patients saved from death or disability
per 1000 treated, and prevention of death or disability is
seen in only four per 1000 ischaemic strokes after
exclusion factors are taken into account.75 The advantages
of aspirin use are low cost, ease of administration, and
low toxic eects, leading to widespread early use.75 The
eectiveness of aspirin probably stems from early
secondary prevention, but penumbral salvage is also
possible.95
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Seminar

Decompressive surgery for ischaemic stroke

Hemispheric decompression in young patients with
malignant middle-cerebral-artery-territory infarction and
space-occupying brain oedema is supported by evidence.
This combination occurs in about 110% of patients with
supratentorial hemispheric infarcts and might arise
between 2 and 5 days after stroke.96 The natural history of
ischaemic stroke is poor, with about 80% mortality rates
usually reported.97 Identication of early predictors of
fatal brain oedema has been dicult, although early CT
hypodensity of more than 50% of the supratentorial
hemisphere has been consistently noted.98 Evidence for
eectiveness of decompressive surgery comes from a
prospective individual-patient meta-analysis of three
randomised control trials.50 These trials were
hemicraniectomy after middle cerebral artery infarction
with life-threatening edema trial (HAMLET; interval to
treatment up to 99 h), decompressive craniectomy in
malignant middle cerebral artery infarction (DECIMAL;
interval to treatment up to 30 h), and decompressive
surgery for the treatment of malignant Infarction of the
middle cerebral artery (DESTINY; interval to treatment
up to 36 h).50 For the purposes of the individual-patient
analysis, a cuto time to surgery of 48 h was adopted;
other inclusion and exclusion criteria of the three trials
were largely similar.
In the pooled analysis of 93 patients, more patients in
the decompressive surgery group than in the control
group had a modied Rankin scale (mRS) of 4 or less
(75% vs 24%; pooled absolute risk reduction 51% [95% CI
3469]), an mRS of 3 or less (43% vs 21%; 23% [541]), and
survived (78% vs 29%; 50% [3367]); number needed to
treat was two patients for survival with an mRS of 4 or
less, four for survival with an mRS of 3 or less, and two for
survival irrespective of functional outcome.50 The eect of
surgery was highly consistent across the three trials.
Although decompressive surgery is appropriate for only a
very small proportion of patients who present with
ischaemic stroke, the benets of surgery have now been
so clearly established that it should form part of routine
clinical practice.

Interventions under evaluation

Various interventions that are presently under investigation
in phase II proof-of-concept trials show great promiseie,
recombinant factor VII for acute intracerebral
haemorrhage, surgery for intracerebral haemorrhage,
extension of the time window for thrombolysis,
sonothrombolysis (combination of ultrasound and
thrombolysis), thrombectomy devices, blood pressure
reduction, and neuroprotection. Haematoma growth
within the rst few hours of stroke onset is a key
independent prognostic factor for poor clinical outcome.40,99
Recombinant factor VII, which is usually given to patients
with haemophilia or to reduce haemorrhagic complications
of major surgical procedures (such as, for example,
prostatectomy) was shown to attenuate haematoma
www.thelancet.com Vol 371 May 10, 2008

growth, with secondary clinical benets, in a phase II

trial.51 The ndings of a phase III study were negative for
the primary endpoint and functional outcome, although
attenuation of haematoma growth was conrmed (not yet
published).
The surgical trial in intracerebral haemorrhage
(STICH) trial provided little support for early surgical
drainage of haematomas after primary haemorrhage.52
Purpose of the STICH II trial was to investigate the
ecacy of surgery in patients with lobar haemorrhage
because uncertainty remains about how to treat these
patients.52 Posterior-fossa decompressive surgery is
generally done to avoid clinical deterioration and death
when cerebellar haematoma or infarction causes
brainstem compression or raised intracranial pressure,
or both, with obstruction of cerebrospinal-uid ow.38
Various trials are investigating extension of the time
window for thrombolysis: (1) standard tPA therapy with
expanded entry criteria with therapeutic time windows of
up to 6 h; (2) imaging techniques to assess the presence
of penumbra with time windows of up to 6 h or even 9 h;
(3) use of alternative thrombolytic agents such as
desmoteplase; (4) combined (bridging) approach with
intravenous therapy followed by intra-arterial
therapy;53,100102 and (5) combination therapies using, for
example, glycoprotein (GP) IIb/IIIa antagonists with
tPA, tested with time windows of up to 24 h (ReoPro
Retavase Reperfusion of Stroke Safety StudyImaging
Evaluation [ROSIE]).103
Low-frequency ultrasoundmight enhance thrombolysis by mobilisation of endogenous tPA, which
increases the surface area that is available to exogenous
tPA and causes mechanical disruption of the clot. Results
of a phase II trial in which patients received transcranial
Doppler ultrasound (with a 2 MHz probe focused on the
symptomatic middle-cerebral artery) and intravenous
tPA showed improved recanalisation rates and a trend
towards better functional outcomes;54 a phase III trial is
about to begin. A similar phase II trial of sonothrombolysis
(with a 5 MHz probe) led to unacceptably high
intracerebral haemorrhage rates.104
Thrombectomy devices are mechanical devices that
have been developed to allow the direct removal of a
blood clot from major vessels such as middle-cerebral or
basilar arteries. The device that has received the most
attention is the mechanical embolus removal in cerebral
ischemia (MERCI) retrieval catheter (Concentric Medical,
Mountain View, CA, USA) which has a corkscrew shape.
In a phase II trial, investigators showed that this catheter
could be used to remove the clot in a timely fashion with
a complication rate similar to that seen with intravenous
tPA.55 Subsequently, the FDA approved the device for clot
removal, but not as a stroke therapy, an action which
evoked some controversy among stroke physicians who
were accustomed to the rigorous regulatory requirements
for pharmaceutical agents.105,106 Various other devices have
been developed, but are less well studied.107
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Seminar

Uncertainty exists about how to manage high blood

pressure in the early stages of stroke.108 About 70% of
patients with ischaemic stroke have high blood pressure
at onset, which might improve with bed rest.109 Concern
about perfusion pressure reduction to the critically
vulnerable ischaemic penumbra has led to the practice of
non-intervention unless systolic blood pressure is greater
than 200 mm Hg or diastolic blood pressure is greater
than 120 mm Hg. A similarly conservative approach
holds for treatment of primary intracerebral haemorrhage,
although the recorded blood pressure is generally higher
than for ischaemic stroke, and some guidelines suggest
aggressive blood pressure control.110
Improved evidence for the optimum management of
blood pressure after stroke should come from trials that
are presently in progress: the ecacy of nitric oxide in
stroke (ENOS) trial for the study of blood pressure
reduction with a nitroglycerin patch in patients with
ischaemic or haemorrhagic stroke56 and the intensive
blood pressure reduction in acute cerebral haemorrhage
(INTERACT) trial for the study of intravenous blood
pressure reduction in patients with haemorrhagic
stroke.111 Evidence to support the view that the risk of
delayed cerebral ischaemia in patients with subarachnoid
haemorrhage is reduced by the maintenance of blood
pressure and blood volume (triple-H therapy) is
insucient.112
Use of drugs that interfere with the pathophysiological
cascades that cause much of the brain injury in stroke is
an appealing idea because of the potential for low-toxic
eects, ease of administration, and for early
administration in an ambulance setting. However,
translation of therapeutic interventions from animal
models to clinical practice is very dicult,113,114 despite the
biological plausibility of attenuation of the ischaemic
cascade and substantial evidence that various classes of
neuroprotectants reduce infarct volumes and improve
neurological outcomes in models of focal cerebral
ischaemia.33,106 The spin trap agent disufenton sodium
(NXY-059), for which there was substantial evidence for
eectiveness in animals,115 showed a modest reduction in
disability in a phase III study (stroke-acute ischemic
NXY-059 treatment [SAINT] I) of about 1700 patients;57
however, a second study (SAINT II)116 with a sample size
larger than 1700 patients showed no ecacy, suggesting
that SAINT I was falsely positive.
Repeated failures of translational research in
neuroprotection show the need for a new approach based
on a consensus of opinions of academic and industry
leaders.106 Evidence that neuroprotectants work in human
brain tissue is absent. Any continued translational research
in neuroprotection should include a rigorous experimental
technique in animals, and should then conrm
neuroprotection in cell cultures of human brain tissue or
brain slices exposed to the eects of hypoxia or glucose
deprivation, or both.117 The next logical step would be to
show that the putative neuroprotectants reach their
1618

therapeutic targetie, the ischaemic penumbrawith

PET or single-photon-emission CT.118 A proof-of-principle
approach, perhaps with a preloading dose of neuroprotectant in high-risk patients (such as early after TIA or
minor stroke, or those undergoing cardiac surgery, carotid
endarterectomy, or angioplasty), would provide reassurance
that the compound was eective in people.28,119,120 Phase II
trials to study treatment eects on ischaemic lesion
formation should only begin after identication of a
proof-of-principle approach and should include patients
with penumbra conrmed by use of imaging techniques,
and then phase III trials with a clinical endpoint should be
done.121,122

Prevention
Primary prevention
The steadily reducing mortality from stroke is largely
attributable to improved control of risk factors,123
especially for hypertension, in which waves of
blood-pressure-lowering agents, each more eective than
the previous one, have permeated western societies from
the 1950s onward.124 Modication of other risk factors
such as socioeconomic status, cholesterol, diabetes, atrial
brillation, and reduction in smoking rates might also
have had some eect.10,125 Level I evidence for the
treatment of hypertension in patients without previous
stroke or TIA suggests the use of warfarin for patients
with atrial brillation, lipid reduction with statins in
patients with pre-existing ischaemic heart disease, and
use of aspirin in women 45 years or older but not
men.126130 Implementation of stroke prevention strategies
is urgently needed in developing countries because these
countries account for about two-thirds of nearly 5 million
stroke-induced deaths per year.1

Secondary prevention
The prevention of recurrent stroke has been one of the
major therapeutic advances in stroke management in the
past 30 years. In 1977, there was no proven secondary
prevention strategy for stroke. Aspirin was introduced
in 1978,58 aspirin plus dipyridamole in 1987,131 warfarin
for patients with atrial brillation in 1993,132 carotid
endarterectomy for symptomatic carotid-artery stenosis
of greater than 70% in 1991,62,63 clopidogrel in 1996,60
blood pressure reduction with perindopril and
indapamide or ramipril in 2001,64,133 and cholesterol
reduction with atorvastatin in 2006.65 Hence, a formidable
array of secondary prevention strategies is now available,
with most patients qualifying for at least one, and many
for up to three or more interventions at hospital
discharge.

Antiplatelet agents
The various antiplatelet agents assessed in clinical trials
for secondary stroke prevention provide about 22% (SE 4)
reduction in relative risk (RR) of further vascular events.134
For patients with TIA or minor stroke, the RR reduction
www.thelancet.com Vol 371 May 10, 2008

Seminar

with aspirin alone (at any dose) might be as low as 13%

(95% CI 40210), but this protection is almost doubled
by the addition of extended-release dipyridamole.59,135,136
Clopidogrel monotherapy is slightly better than aspirin
monotherapy (RR reduction 87%, 03165) and
possibly more eective than aspirin against vascular
disease aecting the heart and the peripheral circulation;
however, the absolute improvement in outcome is small
and needs 108 patients to be treated in 2 years to prevent
one major vascular event (stroke, myocardial infarction,
or vascular death).60 A reasonable consideration is
combination treatment with aspirin plus extended-release
dipyridamole as the standard treatment, with clopidogrel
used when there is aspirin allergy or concurrent
symptomatic coronary artery disease, and aspirin monotherapy used when cost considerations are paramount.
Combination treatment with aspirin plus clopidogrel is
associated with increased risk of major bleeding that is
not oset, at least in unselected patients, by improved
eectiveness.137,138 Treatment with GPIIb/IIIa antagonists
is associated with increased mortality.139 A ceiling eect to
the benecial eects of platelet inhibition might exist,
beyond which adverse eects, predominantly major
haemorrhage, oset any additional eectiveness.137140

Anticoagulants
Warfarin remains one of the most biologically eective
secondary prevention strategies for patients with atrial
brillation and reduces RR of recurrent stroke in patients
with TIA or minor stroke by about 70% (hazard ratio 034,
95% CI 020057).61 This eect of warfarin is partly
oset by a small risk of major bleeding, especially
intracerebral haemorrhage (0306% per year), which
rises with age, high blood pressure, use of warfarin in
combination with antiplatelet agents, and increasing
intensity of anticoagulation.141 Evidence suggests that the
combination of warfarin and aspirin might also be
associated with an increased risk of bleeding without
evidence of benet.142 In patients without atrial brillation,
presenting with TIA or minor stroke, warfarin is not
better than aspirin as a secondary prevention agent.143

patients is low, the absolute benet is only 1% per year,

set against an operative risk in patients with
asymptomatic carotid stenosis of around 3%; the clinical
usefulness of carotid endarterectomy is not clear. The
strong epidemiological evidence of a direct association
between blood pressure and stroke recurrence led to
trials of blood pressure reduction in unselected patients
(ie, including those without hypertension) following
TIA or minor stroke.146,147 Results of the Perindopril
Protection Against Recurrent Stroke Study (PROGRESS),
which tested perindopril and indapamide, showed a
reduction in recurrent stroke of around 30% during
5 years that was independent of baseline blood pressure.64
This eect was broadly similar to that seen for ramipril
in the Heart Outcomes Prevention Evaluation (HOPE)
study in a subset of patients with cerebral vascular
disease.133,148
Although cholesterol is a weak risk factor for ischaemic
stroke, evidence suggests that both fatal and non-fatal
stroke is reduced in patients with coronary artery disease
who are given statins.147,149,150 This eect seems to be
independent of the baseline cholesterol concentration,
which raises the possibility that ecacy might be caused
by anti-inammatory, rheological-plaque-stabilising, or
neuroprotective attributes of statins.150 The heart
protection study (HPS)151 showed that treatment with
simvastatin (40 mg) in patients with TIA or stroke led to
reductions in the risk of cardiac events but not of
recurrent stroke. The stroke prevention by aggressive
reduction in cholesterol levels (SPARCL)65 study showed
that intensive cholesterol reduction (atorvastatin 80 mg)
in patients with TIA or minor stroke and no history of
ischaemic heart disease reduced the risk of both fatal and
non-fatal stroke.
Surgical clipping of intracerebral aneurysms has been
an established practice for the avoidance of recurrent
haemorrhage after subarachnoid haemorrhage.23
Endovascular approaches (coiling) have been compared
with surgery, and have been shown to have improved
clinical outcomes at 1 year and reduced complication
rates at the expense of a small increase in the risk of late
rebleeding.152

Carotid endarterectomy
In patients with TIA or minor stroke who have at
least 70% stenosis of the symptomatic carotid artery,
carotid endarterectomy is an eective secondary
prevention strategy.62,63 Relative reduction in the risk of
ipsilateral fatal or non-fatal stroke is about 60% during
3 years,144 which should be balanced with a surgical risk
of stroke or death, in expert hands, of around 5%.119
Importantly, the interval between TIA or stroke and
endarterectomy is inversely proportional to the benet,
with uncertainty as to whether any benet remains
beyond 12 weeks.119
A relative reduction in the risk of stroke or death is
also seen in patients with asymptomatic carotid
stenosis.145 However, because the absolute risk in these
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Treatments under investigation

Carotid angioplasty with stenting, which is now generally
combined with distal protection devices, is a minimally
invasive procedure that will probably replace carotid
endarterectomy as the treatment of choice in most
patients. Initial trials suggested that the perioperative
risks associated with the procedure are similar to carotid
endarterectomy,153,154 but the risks might be increased in
less skilled hands;120 further randomised controlled trials
are underway to explore the procedural risks and
long-term eectiveness of stenting. In view of the
complexities of warfarin use, simpler and safer
alternatives would provide a major advance in stroke
treatment. The direct-thrombin inhibitor ximelagatran
1619

Seminar

showed promise in early trials, but resulted in an

unacceptably high frequency of liver enzyme
abnormalities (about 6%);67 other direct-thrombin
inhibitors are being developed. Prevention of stroke
recurrence by modication of risk factors such as blood
sugar reduction in diabetics,155 smoking cessation,
reduced alcohol consumption (although moderate
consumption can be protective), or increased exercise is
not substantiated by evidence from clinical trials.
However, on the basis of observational studies, which
show many potential benets, modest costs, and small
risks of adverse eects, patients should be advised to stop
smoking, to drink in moderation, to eat a well-balanced
diet, and to exercise regularly.156159

10

11

12
13
14

15

Conclusions
Although there have been advances in our understanding
of the epidemiology and pathophysiology of stroke during
the past decade, the most striking changes have been in
the increasing array of therapeutic interventions. The
greatest advance is the recognition that SCU management
reduces mortality and improves clinical outcomes. The
importance of this nding is emphasised as networks of
SCUs become established across many countries and
form a framework for the propagation of knowledge of
stroke management. Much of the translational research
described in this seminar has taken place within such
frameworks. However, despite the advances in
management, stroke continues to pose major therapeutic
challenges, both to neuroscientists and to clinicians,
partly because of the low priority accorded to stroke
research.
Eective introduction of many therapeutic strategies
for stroke has served, paradoxically, to highlight a
worldwide shortage of health-care professionals who are
able to facilitate implementation of the strategies. This
imbalance, especially in the developing world where the
health-care burden during the coming decades is likely to
be most keenly felt, needs to be urgently addressed.

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22
23
24

25

Conict of interest statement

We declare that we have no conict of interest.
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