Seminar

Stroke
Graeme J Hankey

In the past decade, the denition of stroke has been revised and major advances have been made for its treatment and Published Online
prevention. For acute ischaemic stroke, the addition of endovascular thrombectomy of proximal large artery occlusion September 13, 2016
http://dx.doi.org/10.1016/
to intravenous alteplase increases functional independence for a further fth of patients. The benets of aspirin in S0140-6736(16)30962-X
preventing early recurrent ischaemic stroke are greater than previously recognised. Other strategies to prevent recurrent
School of Medicine &
stroke now include direct oral anticoagulants as an alternative to warfarin for atrial brillation, and carotid stenting as Pharmacology, The University
an alternative to endarterectomy for symptomatic carotid stenosis. For acute intracerebral haemorrhage, trials are of Western Australia, Perth,
ongoing to assess the eectiveness of acute blood pressure lowering, haemostatic therapy, minimally invasive surgery, WA, Australia
(Prof G J Hankey MD);
anti-inammation therapy, and neuroprotection methods. Pharmacological and stem-cell therapies promise to facilitate
Department of Neurology,
brain regeneration, rehabilitation, and functional recovery. Despite declining stroke mortality rates, the global burden of Sir Charles Gairdner Hospital,
stroke is increasing. A more comprehensive approach to primary prevention of stroke is required that targets people at Perth, WA, Australia
all levels of risk and is integrated with prevention strategies for other diseases that share common risk factors. (Prof G J Hankey); and Western
Australian
Neuroscience Research
Introduction the brain, retina, or spinal cord. Stroke is distinguished Institute (WANRI), Perth, WA,
The world is facing an epidemic of stroke. Despite stable from transient ischaemic attack (TIA) if the symptoms Australia (Prof G J Hankey)
incidence rates and declining mortality rates over the past persist longer than 24 h (or lead to earlier death). An Correspondence to:
two decades, the number of incident strokes, prevalent updated denition of stroke is an acute episode of focal Prof Graeme J Hankey, School of
Medicine and Pharmacology,
stroke survivors, disability-adjusted life-years (DALYs) lost dysfunction of the brain, retina, or spinal cord lasting
The University of Western
due to stroke, and stroke-related deaths is increasing.1 This longer than 24 h, or of any duration if imaging (CT or Australia, Perkins Institute of
Seminar highlights recent developments in the denition, MRI) or autopsy show focal infarction or haemorrhage Medical Research, QEII Medical
treatment, and prevention of stroke to help clinicians to relevant to the symptoms.3 The denition includes Centre, Perth, WA 6009,
Australia
manage stroke and reduce its impact on aected subarachnoid haemorrhage.3 A TIA has been redened
graeme.hankey@uwa.edu.au
individuals, their carers, and the population as a whole. as focal dysfunction of less than 24 h duration and with
no imaging evidence of infarction.3
Epidemiology
In 2010, an estimated 169 million incident strokes Diagnosis of stroke
occurred, which added to a pool of 33 million stroke Typical symptoms of stroke include sudden unilateral
survivors worldwide (table 1).1 There were 59 million weakness, numbness, or visual loss; diplopia; altered
deaths and 102 million DALYs lost due to stroke, making speech; ataxia; and non-orthostatic vertigo.4 Associated
stroke the second leading cause of death after ischaemic symptoms (eg, headache) vary and usually reect the
heart disease and third leading cause of DALYs lost cause or consequences of the stroke. Atypical symptoms
worldwide. Most of the global burden of stroke, in terms of stroke include isolated vertigo, binocular blindness,
of deaths and DALYs lost, was borne by low-income and amnesia, anosognosia, dysarthria, dysphagia, stridor,
middle-income countries (LMICs) and caused by foreign accent, or headache; hemiballismus; alien hand
haemorrhagic stroke.2 syndrome; confusion; and altered consciousness.4
Between 1990 and 2010, the global incidence rate of Diagnostically, the Face Arm and Speech Test (FAST)
stroke remained stable but the number of incident rst aids screening for stroke and is as sensitive and specic
strokes increased by 68%. The prevalence of stroke as the Recognition of Stroke in the Emergency Room
increased slightly, yet the number of stroke survivors (ROSIER) score.4,5 Non-contrast cranial CT scan has
increased by 84%. The number of DALYs lost per stroke near-perfect sensitivity to detect fresh intracranial
decreased, but the total number of DALYs lost increased haemorrhage, but its sensitivity for diagnosis of
by 12%. The mortality rate fell, but the number of ischaemic stroke is poor if ischaemia is recent, small, or
stroke-related deaths increased by 26% (table 1).1 The in the posterior fossa. Diusion weighted MRI
reduction in rates can probably be attributed to improved
prevention and management of stroke, particularly in
high-income countries. The increase in numbers, despite Search strategy and selection criteria
reductions in rates, probably reects global population I searched the Cochrane Library, PubMed, and MEDLINE using
growth, increasing life expectancy, and a change in the the search term stroke in combination with the terms
age structure of most populations. diagnosis, risk factors, prognosis, treatment, and
prevention for articles published between Jan 1, 2010, and
Denition of stroke and transient ischaemic attack June 1, 2016. I also searched the reference lists of articles
The traditional denition of stroke is clinical and based identied by the search. I selected mainly articles published in
on the sudden onset of loss of focal neurological function the past 5 years, but included older key publications.
due to infarction or haemorrhage in the relevant part of

www.thelancet.com Published online September 13, 2016 http://dx.doi.org/10.1016/S0140-6736(16)30962-X 1

 Seminar

1990 2005 2010 Change from 19902010

Number of Rate per 100 000 Number of Rate per 100 000 Number of Rate per 100 000 Change in Change in rate in HICs Change in rate in LMICs
events person-years events person-years events person-years number of
events
All stroke
Incidence 10 078 935 251 (230273) 14 734 124 256 (232284) 16 894 536 258 (234284) 68% increase 12% (6 to 17) decrease 12% (3 to 22) increase
Prevalence 17 915 338 435 (389497) 28 495 582 490 (437558) 33 024 958 502 (451572) 84% increase
DALYs lost 86 010 384 2063 (19502280) 101 951 696 1750 (15691831) 102 232 304 1554 (13741642) 12% increase
Deaths 4 660 449 117 (112130) 5 684 970 99 (89104) 5 874 182 88 (8094) 26% increase 37% (31 to 41) decrease 20% (15 to 30) decrease
Ischaemic stroke
Incidence 7 238 758 181 (167196) 10 097 297 175 (160192) 11 569 538 176 (161192) 37% increase 13% (6 to 18) decrease 6% (7 to 18) increase
DALYs lost 32 128 220 796 (734906) 38 571 908 668 (617774) 39 389 408 598 (560692) 18% increase 34% (16 to 36) decrease 16% (1 to 35) decrease
Deaths 2 241 077 58 (5464) 2 701 873 47 (4454) 2 835 419 42 (4049) 21% increase 37% (19 to 39) decrease 14% (9 to 19) decrease
Haemorrhagic stroke
Incidence 2 840 177 69 (6277) 4 636 828 80 (7192) 5 324 997 82 (7293) 47% increase 8% (1 to 15) decrease 22% (5 to 30) increase
DALYs lost 53 882 164 1267 (10681484) 63 379 792 1081 (9351234) 62 842 896 956 (8281104) 14% increase 39% (32 to 44) decrease 25% (7 to 38) decrease
Deaths 2 419 372 60 (5170) 2 983 097 52 (4559) 3 038 763 46 (4053) 20% increase 38% (32 to 43) decrease 23% (7 to 36) decrease

Data in parentheses are 95% CI. HIC=high-income country. LMIC=low-income and middle-income country. DALY=disability-adjusted life-year.

Table 1: Age-adjusted annual incidence and mortality rates, prevalence, and DALYs lost for all stroke, ischaemic stroke, and haemorrhagic stroke1,2

(DWI-MRI) detects acute brain ischaemia in about 90%
of patients with ischaemic stroke and about a third of
patients with transient symptoms lasting less than 24 h.6,7
DWI-MRI can be suggestive of stroke in patients with a
stroke mimic (eg, seizures, migraine, hypoglycaemia,
tumour, encephalitis, abscess, and multiple sclerosis).
Gradient-echo T2-weighted susceptibility MRI is as
sensitive as CT for acute haemorrhage and more sensitive
for previous haemorrhage. About 2025% of patients
presenting with a stroke syndrome have a stroke mimic;
most commonly seizures, syncope, sepsis, peripheral
vestibulopathy, and toxic or metabolic encephalopathy.8
The diagnosis of stroke is most dicult in the initial
hours, particularly if the onset is uncertain, the features
are atypical or changing, the patient is unwell or agitated,
access to imaging is delayed, or brain imaging is normal.
Subtypes of stroke
Clinical ischaemic stroke syndromes include total
anterior circulation syndrome, partial anterior circulation
syndrome, lacunar syndrome, and posterior circulation
syndrome.9 Pathological subtypes comprise ischaemic
stroke (cerebral, retinal, and spinal infarction) and
haemorrhagic stroke (intracerebral haemorrhage and
subarachnoid haemorrhage). The proportions of
pathological and aetiological subtypes of stroke vary
among populations of dierent age, race, ethnic origin,
and nationality.
Aetiologically, ischaemic stroke is caused by embolism
from the heart, artery-to-artery embolism, and in-situ
small vessel disease. Aetiological subtypes of ischaemic
stroke are classied according to the TOAST
classication,10 the ASCOD phenotyping system
(A: atherosclerosis; S: small-vessel disease; C: cardiac
pathology; O: other cause; D: dissection),11 and the
Causative Classication System.12 A third of ischaemic
strokes remain of undetermined cause (ie, cryptogenic),
of which a subgroup is now dened as having embolic
strokes of undetermined source.13
Haemorrhagic stroke is classied according to its
anatomical site or presumed aetiology. The most
common sites of intracerebral haemorrhage are
supratentorial (8595%), including deep (5075%) and
lobar (2540%).14 The most common causes are
hypertension (3060%), cerebral amyloid angiopathy
(1030%), anticoagulation (120%), and vascular
structural lesions (38%); the cause is undetermined in
about 520% of cases.14
Risk factors
Hypertension, hypercholesterolaemia, carotid stenosis,
and atrial brillation are known to be causal risk factors
for stroke because clinical trials have shown that
treatment of these conditions reduces the incidence of
stroke.1518 Cigarette smoking, excessive alcohol use,
insulin resistance, and diabetes mellitus are also likely
causal risk factors.1922 Other risk factors that, if modied,
could reduce the incidence of stroke include
environmental air pollution, childhood health
circumstances and tness, high-risk diet and poor
nutrition, physical inactivity, obesity, blood pressure
variability, sleep-disordered breathing, chronic inam-
mation, chronic kidney disease, migraine, hormonal
contraception or hormone replacement therapy,
psychosocial stress, depression, job strain, and long
working hours.23,24
Besides rare highly penetrant mendelian mutations
that cause early-onset stroke, several genetic loci have
been associated with ischaemic stroke (eg, chromosome
12q24.12 near ALDH2) and its subtypeseg, the ZFHX3

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 Seminar

gene on chromosome 16q22 and PITX2 gene on

Score for
chromosome 4q25 for cardioembolic stroke; the HDAC9 characteristic
gene on chromosome 7p21 and locus on chromosome
ABCD-I score32*
1p13.2 near the TSPAN2 gene for large-vessel stroke; and
Age 60 years 1
chromosome 6p25 near the FOXF2 gene for small-vessel
Blood pressure 140/90 mm Hg 1
disease.25,26 Genetic variants 2 and 4 within the
Clinical features
apolipoprotein E (APOE) gene are risk factors for lobar
Speech impairment without weakness 1
intracerebral haemorrhage.
Unilateral weakness 2
Ten treatable risk factors account for about 90% of the
Duration
population-attributable risk of stroke.23,24 Stroke can also be
triggered by several activities (eg, neck trauma and coitus) 1059 min 1

and risk factors (eg, alcohol, amphetamines, infection, and 60 min 2

air pollution, and perhaps psychosocial stress).27 Diabetes mellitus present 1

Prognosis after stroke and TIA
The case fatality rates after all stroke are about 15% at
1 month, 25% at 1 year, and 50% at 5 years.28 After
intracerebral haemorrhage, the case fatality rates are
about 55% at 1 year and 70% at 5 years.29 About 40% of
stroke survivors are disabled (modied Rankin Scale
[mRS] score 35) between 1 month and 5 years after
stroke; 20% are disabled before the stroke.28 Five variables
(age, verbal component of the Glasgow Coma Scale, arm
power, ability to walk, and pre-stroke dependency) predict
independent survival at 3 months and 12 months after
stroke.30 Other prognostic factors include stroke severity,
clinical subtype, employment status, marital status, and
recurrent stroke.28
After ischaemic stroke and TIA, the risk of recurrent
stroke without treatment is about 10% at 1 week, 15%
at 1 month, and 18% at 3 months.31 The risk is greater
among individuals with recent symptomatic athero-
sclerosis and high ABCD-I and recurrence risk estimator
scores (table 2);32,33 the ABCD score does not reliably
discriminate patients at low and high risk.34 With urgent
assessment and appropriate treatment, the risk of
recurrent stroke is 80% lower.35,36
The longer-term risk of recurrent stroke is about 10%
at 1 year, 25% at 5 years, and 40% at 10 years.37 The risk
is higher among individuals with symptomatic
atherosclerotic disease, vascular risk factors, or an active
source of thrombosis, or who have discontinued
antiplatelet and antihypertensive drugs. For patients
with atrial brillation, the risk of stroke increases with
higher CHADS2, CHA2DS2-VASc, and ABC (age,
biomarkers [N-terminal fragment B-type natriuretic
peptide (NT-proBNP) and cardiac troponin high-
sensitivity (cTn-hs)], and clinical history [prior stroke or
TIA]) stroke scores.38 After haemorrhagic stroke, the
annual risks of recurrent intracerebral haemorrhage
and ischaemic stroke are similar, and vary from 13% to
74%.29 The risk of recurrent intracerebral haemorrhage
is higher after lobar intracerebral haemorrhage than
after non-lobar haemorrhage and in patients with
inadequate blood pressure control than in those in
whom blood pressure is maintained within prespecied
limits.39
Dual TIA (index TIA plus 1 other TIA in preceding 7 days) 2
Imaging: ipsilateral 50% stenosis of internal carotid 2
artery
Imaging: acute diusion-weighted imaging 2
hyperintensity
Recurrence risk estimator at 90 days33
Clinical
History of TIA or stroke within the preceding month of 1
index stroke
CCS aetiological stroke subtype
Large artery atherosclerosis 1
Cardioaortic embolism 0
Small artery occlusion 0
Other causes 1
Undetermined causes 0
Brain MRI within rst 72 h
Multiple acute infarcts 1
Simultaneous infarcts in dierent circulations 1
Multiple infarcts of dierent ages 1
Isolated cortical infarcts 1
If the stated criteria are not met, a score of 0 is assigned. NA=not applicable.
TIA=transient ischaemic attack. CCS=Causative Classication System for Ischemic
Stroke. *Total range 013. Total range 06. Available at: http://www.nmr.mgh.
harvard.edu/RRE-90.
Table 2: Scores to identify patients at early risk of recurrent stroke32,33
Specic treatment for acute ischaemic stroke
Intravenous alteplase (rtPA), 09 mg/kg, administered
within 45 h of ischaemic stroke, increases the odds of
no signicant disability (mRS 01) at 36 months by
about a third and does not aect mortality, despite
increasing the odds of symptomatic intracerebral
haemorrhage (table 3).40 The proportional benets of
alteplase are larger with earlier treatment and the
proportional risks of symptomatic intracerebral
haemorrhage with alteplase are larger with a high
SEDAN score (blood sugar, early infarct signs, [hyper]
dense cerebral artery sign, age, and National Institutes of
Health Stroke Scale [NIHSS] score). 40,49
Using a lower dose of alteplase (06 mg/kg) reduces the
incidence of symptomatic intracerebral haemorrhage but
does not lead to better functional outcome at 90 days
compared with standard-dose alteplase.50 Functional
outcome is also not improved by adjunctive transcranial

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 Seminar

alteplase within 6 h of ischaemic stroke doubles the rate

Proportion of patients Odds ratio Absolute
with reported functional (95% CI) dierence of angiographic revascularisation at 24 h and functional
outcome (%) independence at 90 days (table 3), and increases the
Treatment Control likelihood of improving by 1 point or more on the mRS
group (%) group (%) by 25 times, without increasing risk of symptomatic
Ischaemic stroke intracerebral haemorrhage or all-cause mortality.41,42 The
Thrombolysis with alteplase40 eect is consistent among elderly people (>80 years) and
Good recovery (mRS 01) in patients 34% 28% 137 (120156) 7%
patients ineligible for intravenous alteplase.
who received alteplase 045 h after Improved outcomes with endovascular thrombectomy
stroke in recent trials can be attributed to improved patient
Good recovery (mRS 01) in patients 33% 23% 175 (135227) 10% selection by CT or MR angiogram to conrm large artery
who received alteplase 03 h after occlusion (gure), shorter time to revascularisation, and
stroke
second-generation devices and techniques that enable
Good recovery (mRS 01) in patients 35% 30% 126 (105151) 6%
who received alteplase 345 h after higher rates of reperfusion.41,42,56 Ongoing trials are
stroke evaluating whether patients with small ischaemic cores
Symptomatic ICH within 7 days 7% 1% 555 (401770) 5% and substantial salvageable penumbra, as identied by
Fatal ICH within 7 days 3% <1% 714 (3981279) 2% CT or MR perfusion, could benet from alteplase and
Endovascular thrombectomy41,42 endovascular thrombectomy beyond 6 h (appendix).56
Second-generation devices42 Implementation of endovascular therapy in clinical
Good recovery (mRS 01) 27% 13% 249 (184335) 14% practice will require local algorithms to enable emergency
Independent (mRS 02) 46% 26% 235 (185298) 20% medical services to rapidly and accurately identify, triage,
All devices41 and transport the 10% of stroke patients suitable for
endovascular therapy directly to comprehensive stroke
Independent (mRS 02) 43% 32% 171 (118249) 11%
centres where resourced, accessible, and specialised stroke
Aspirin43
teams can restore reperfusion within 90 min of arrival.57
Independent (mRS 02) 55% 54% 105 (101110) 1%
Death or dependence (mRS 36) 45% 46% 095 (091099) 1%
Specic treatment for acute haemorrhagic
Hemicraniectomy44
stroke
Death (mRS 6) 30% 71% 019 (012030) 41%
Intensive blood pressure reduction within 36 h of onset
Severe disability or death (mRS 56) 42% 84% 015 (009024) 42%
of intracerebral haemorrhage to a systolic target of lower
Major disability or death (mRS 46) 73% 87% 042 (024076) 14%
than 140 mm Hg may not be safe for all patients, nor more
Major or severe disability (mRS 45) 62% 55% 171 (078374) NS; p=018
eective in reducing death and disability, compared to a
Intracerebral haemorrhage
systolic target of lower than 180 mm Hg (table 3).45,46
Intensive BP-lowering to target systolic
For intracerebral haemorrhage not associated with
BP <140 mm Hg (vs target
<180 mm Hg)45,46 antithrombotic therapy, recombinant activated factor
Death or dependence (mRS 36)45 52% 56% 087 (076101) NS; p=006 VII (rFVIIa) decreases haematoma growth, but increases
Major disability or death (mRS 46)46 39% 38% 104 (085127)* NS; p=072 thromboembolic events, and does not improve functional
Surgery for supratentorial ICH47 outcome.58 Platelet transfusion after intracerebral
Unfavourable outcome 59% 66% 074 (064086) 7%
haemorrhage associated with antiplatelet drugs increases
Surgery for lobar haematoma without intraventricular haemorrhage47
death and dependence at 3 months.59 For spontaneous
Death or disability 62% 68% 078 (059102) NS; p=007
intracerebral haemorrhage associated with vitamin K
All stroke
antagonist anticoagulation, reversal of the INR to lower
than 13 and reduction of the systolic blood pressure to
Stroke-unit care
lower than 160 mm Hg within 4 h is associated with
Death or dependence (mRS 36)48 56% 61% 079 (068090) 5%
reduced hematoma enlargement.60 Four-factor
Endovascular thrombectomy given plus thrombolysis and usual care in most participants. mRS=modied Rankin Scale prothrombin complex concentrate seems superior to fresh
score. ICH=intracerebral haemorrhage. NS=not signicant. BP=blood pressure. *Risk ratio (95% CI). frozen plasma to normalise the INR and reduce
Table 3: Eect of treatments or care strategies for ischaemic stroke, intracerebral haemorrhage, or all haematoma expansion.61 Management of acute
stroke on functional outcome intracerebral haemorrhage associated with direct
inhibition of thrombin or factor Xa by direct oral
doppler ultrasound,51 hypothermia,52 or desmoteplase.53 anticoagulants requires immediate cessation of the direct
Tenecteplase is being compared with alteplase in several oral anticoagulants, supportive measures, and
See Online for appendix phase 3 trials (appendix).54 Concomitant antithrombotic consideration of specic reversal agents, such as
drugs should be avoided for the rst 24 h after alteplase to idarucizumab for dabigatran-associated intracerebral
limit haemorrhagic transformation of any infarcted brain.55 haemorrhage, or non-specic haemostatic agents, such as
The addition of endovascular thrombectomy with prothrombin complex concentrate, that show positive
second-generation devices (eg, stent retrievers) to laboratory results.6165

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A B C D E

F G H I J

Figure: Imaging in a patient with acute ischaemic stroke treated with endovascular thrombectomy
Plain CT brain scan, axial plane, showing hyperdensity of the intracranial proximal left middle cerebral artery (A). CT angiogram, axial plane, showing a lling defect due to occlusion of the intracranial
proximal left middle cerebral artery (B). CT perfusion, axial plane, showing prolonged time to peak (TTP) cerebral blood ow in most of the territory of supply of the left middle cerebral artery (blue
area; C). CT perfusion, axial plane, showing prolonged mean transit time (MTT) of cerebral blood ow in most of the territory of supply of the left middle cerebral artery (blue area; D). CT perfusion,
axial plane, showing reduced cerebral blood ow (CBF) in most of the territory of supply of the left middle cerebral artery (blue area; E). CT perfusion, axial plane, showing preserved cerebral blood
volume (CBV) in most of the territory of supply of the left middle cerebral artery (F). CT perfusion, axial plane, showing a mismatch between the smaller infarct core in the left putamen and anterior
temporal lobe (red; increased MTT and reduced CBV) and large ischaemic penumbra (green; increased MTT and normal CBV; G). Intra-arterial digital subtraction angiogram, coronal plane, showing a
lling defect, due to occlusion, in the intracranial proximal left middle cerebral artery (H). Intra-arterial digital subtraction angiogram, coronal plane, after endovascular thrombectomy showing
restoration of cerebral blood ow in the left middle cerebral artery territory (I). Plain CT, axial plane, day 1 post-endovascular thrombectomy, showing residual infarction (low density) in the left
putamen and anterior temporal lobe (J).

Early open-surgery evacuation of supratentorial
haematomas might be benecial for patients with a
Glasgow Coma Scale score of 912 who are treated within
8 h of symptom onset.47,66 Minimally invasive drainage by
catheter holds promise in the treatment of deep
haematomas.67 An external ventricular drain combined
with topical brinolysis reduces mortality but not
functional dependence in intraventricular haemorrhage
and hydrocephalus.68 Surgical evacuation of infratentorial
intracerebral haemorrhage is usually indicated if the
Glasgow Coma Scale score is lower than 14, haematoma
diameter higher than 3040 mm, haematoma volume
higher than 7 cm, or if there is obliteration of the fourth
ventricle. An external ventricular drain is usually inserted
if there is associated hydrocephalus.
General treatment of acute stroke
In high-income countries, stroke-unit care increases the
likelihood of discharge home and reduces death and
dependence compared with care in a general ward
(table 3).48 Processes associated with reduced mortality
include review by a stroke consultant within 24 h of
admission, nutrition screening and formal swallow
assessment within 72 h, and antiplatelet therapy and
adequate uids and nutrition in the rst 72 h.69 It is
uncertain whether stroke-unit care is relevant and
applicable to LMIC settings and which components are
important in low-technology units.70
There is no reliable evidence to guide the optimum
volume, duration, or mode of parenteral uid delivery for
patients with poor oral uid intake. Hypertonic uids
(colloids) increase pulmonary oedema compared with
isotonic uids (crystalloids).71 For patients with dysphagia,
the eect of various swallowing therapies, feeding, and
nutritional and uid supplementation on functional
outcome is uncertain.72 Nutritional supplementation is
associated with reduced pressure sores.72
Many neuroprotective drugs have failed to show a
functional benet in the treatment of acute stroke,
including recent trials of citicoline, high-dose albumin,
and magnesium sulfate.73 Current evidence does not
support routine use of physical or pharmacological
strategies to reduce temperature in acute stroke; trials
are ongoing (appendix).

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 Seminar
Lowering blood pressure during the rst days after
major stroke does not improve functional outcome.74,75
There is no urgency to restart pre-existing anti-
hypertensive therapy in the rst days, unless for
comordid disorders.75 However, lowering of blood
pressure days to weeks after TIA or minor stroke is safe
and associated with a low risk of recurrent stroke.35
Lowering blood glucose to 4075 mmol/L in the rst
24 h after ischaemic stroke by intravenous insulin does
not improve death or dependence but increases
symptomatic hypoglycaemia, particularly if glucose
concentrations are maintained within a tight range.76
Preventing and managing complications
Neurological and medical complications after stroke are
a major cause of morbidity and mortality if they are not
anticipated, prevented, and managed appropriately.
Preventive antibiotics for 47 days in patients with acute
stroke or associated dysphagia do not reduce post-stroke
pneumonia or improve functional outcome.77,78 For
immobile patients, intermittent pneumatic compression
with thigh-length sleeves worn on both legs for 30 days
and nights reduces proximal and symptomatic deep-vein
thrombosis and improves 6 month survival, but does not
improve functional outcome.79 Graduated compression
stockings are ineective. The benets of low-dose
subcutaneous heparins and heparinoids in reducing
venous thromboembolism are oset by haemorrhagic
complications.80
Cerebral oedema can be a secondary consequence of a
large area of brain infarction. Early decompressive
hemicraniectomy for malignant middle cerebral artery
infarction signicantly decreases 12 month mortality,
death or severe disability (mRS score >4), and death or
major disability (mRS score >3), but is associated with
non-signicantly higher major disability (mRS
score 45) among survivors compared with conservative
treatment (table 3).44 The trade-o between improved
survival at the expense of substantial disability is
greater for patients older than 60 years than for those of
a younger age.44 The optimum criteria for patient
selection, timing of surgery, and acceptable degree of
disability in survivors remain undened. However, if
decompressive hemicraniectomy is to be undertaken, it
should be before there is major midline shift causing
secondary ischaemic brain injury and bleeding in
the brainstem.
Preventing recurrent ischaemic stroke of arterial
origin
Urgent initiation of eective secondary prevention after
TIA and minor ischaemic stroke can reduce the risk of
early recurrent stroke by 80% (table 4).35 Immediate
aspirin, 160300 mg a day, reduces the rate and severity
of early recurrent stroke by at least half within the rst
612 weeks (table 4).43,81 Ticagrelor is as safe as aspirin in
patients with acute TIA and mild ischaemic stroke, but is
6 www.thelancet.com Published online September 13, 2016 http://dx.doi.org/10.1016/S0140-6736(16)30962-X
not superior to aspirin in reducing the 90 day rate of
stroke, myocardial infarction, or death.82
Dual antiplatelet therapy seems more eective than
monotherapy in reducing early recurrent stroke
(table 4).83 The most eective combination is aspirin and
clopidogrel in Chinese patients with acute TIA or minor
ischaemic stroke (NIHSS score <3), who are at low risk
of haemorrhagic complications and who are not carriers
of CYP2C19 loss-of-function alleles (*2, *3).99 Trials of
dual and triple acute antiplatelet therapy in other
populations are ongoing (appendix).
Eective long-term antiplatelet regimens for preventing
recurrent stroke include aspirin 75150 mg a day,
clopidogrel 75 mg a day, aspirin 25 mg twice a day plus
extended-release dipyridamole 200 mg twice a day, and
cilostazol (table 4).8892 Long-term triusal, terutroban,
vitamin K antagonists, aspirin plus clopidogrel, and
vorapaxar plus standard antiplatelet treatment are not as
safe and eective as aspirin or clopidogrel monotherapy
or aspirin plus extended-release dipyridamole.100
Anticoagulation in acute ischaemic stroke does not
reduce early recurrent stroke, mortality, or death or
dependency compared with control, even among patients
at higher risk of thrombosis or lower risk of
haemorrhage.101,102 Anticoagulation is also not more
eective than antiplatelet therapy in reducing 90 day
stroke or death after recent symptomatic carotid and
vertebral artery dissection.103
Carotid endarterectomy in patients with recent
symptomatic extracranial atherosclerotic carotid stenosis
reduced the risk of stroke or death at 5 years by half in
patients with 7099% stenosis, and a quarter with 5069%
stenosis, when added to medical therapy 25 years ago
(table 4).84,104 The second ECST-2 trial is currently comparing
the risks and benets of adding immediate carotid surgery
(or stenting) to modern medical therapy (appendix).
Compared with carotid endarterectomy, carotid artery
stenting has lower risks of periprocedural myocardial
infarction, cranial nerve palsy, and access-site
haematoma, but, in patients aged 70 years or older, a
higher risk of periprocedural stroke or death.85 The
long-term rate of stroke or death is also higher with
carotid artery stenting than carotid endarterectomy due
to the periprocedural dierences in risk; the long-term
rates of fatal or disabling stroke, composite of major
vascular events, and functional outcome after carotid
artery stenting and carotid endarterectomy are similar
(table 4).8587 If carotid revascularisation is to be done, it
should be early, within the rst week after stroke or TIA,
when the risk of recurrent stroke is highest.36,104,105
However, the operative risks may be higher if surgery is
done less than 48 h after symptom onset.105
Stenting of recently symptomatic atherosclerotic
intracranial stenosis and extracranial vertebral stenosis is
associated with unacceptable periprocedural risks of
stroke or death, compared with intensive medical
therapy.106108 There is also no benet of ow-augmentation
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Proportion of patients with outcome Risk ratio (95% CI) Absolute risk
reduction (%)
Treatment group (%) Control (%)
Acute therapy in patients with TIA or ischaemic stroke
Acute specialty unit (vs outpatient clinic)35
Stroke at 90 days 2% 10% 020 (008049) 12%
Aspirin (vs control)43,81
Stroke at 6 weeks 1% 2% 045 (035058) 13%
Stroke at 12 weeks 2% 4% 049 (040060)* 18%
Disabling or fatal ischaemic stroke at 12 weeks 1% 2% 034 (025046)* 14%
Ticagrelor (vs aspirin)82
Stroke at 90 days 6% 7% 086 (075099)* 09%
Dual antiplatelet therapy (vs single drug)83
Stroke at about 90 days 6% 9% 069 (060080) 28%
Carotid endarterectomy (vs medical therapy)84
Any stroke or operative death at 5 years in patients with 7099% carotid stenosis 15% 29% 053 (042067) 139%
Any stroke or operative death at 5 years in patients with 5069% carotid stenosis 17% 23% 077 (063094) 56%
Ipsilateral ischaemic stroke and any operative stroke or death at 5 years in patients with 7099% carotid stenosis 10% 24% 040 (030054) 142%
Ipsilateral ischaemic stroke and any operative stroke or death at 5 years in patients with 5069% carotid stenosis 12% 15% 082 (064105) NS; p=011
Carotid stent (vs carotid endarterectomy)8587
Any stroke or death85 25% 21% 141 (107184) 43%
Any stroke at 5 years86 15% 9% 171 (128230)* 58%
Fatal or disabling stroke at 5 years86 6% 6% 106 (072157)* NS; p=077
Ipsilateral carotid stroke at 5 years86 5% 3% 129 (074224) NS; p=036
Longer-term therapy in patients with TIA or ischaemic stroke
Aspirin88
Stroke per year 4% 5% 083 (072096) 08%
Clopidogrel (vs aspirin)89
Recurrent stroke at 2 years 11% 12% 090 (080100) 1%
Aspirin plus ER dipyridamole (vs aspirin)90
Recurrent stroke at 26 years 9% 11% 078 (068090)* 23%
Aspirin plus ER dipyridamole (vs clopidogrel)91
Recurrent stroke at 25 years 9% 9% 101 (092111)* NS; p=071
Cilostazol (vs aspirin)92
Recurrent stroke at 3 years 5% 8% 067 (052086) 27%
Blood pressure lowering by 51/25 mm Hg93
Recurrent stroke at 3 years 9% 10% 078 (068090) 13%
LDL cholesterol lowering by 1 mmol/L94
Recurrent stroke at 5 years 11% 12% 088 (078099) 14%
Pioglitazone for insulin resistance21
Stroke or myocardial infarction 9% 12% 076 (062093)* 28%
Recurrent stroke at 48 years 7% 8% 082 (061110)* NS; p=019
Warfarin for atrial brillation (vs control)95
Recurrent stroke at 2 years 9% 23% 036 (022058) 14%
Direct oral anticoagulants (vs warfarin)96
Stroke or systemic embolism at 2 years 5% 6% 086 (076098) 08%
Left atrial appendage closure (vs warfarin)97
Stroke or systemic embolism at 27 years 175% per year 187% per year 102 (06217)* NS; p=094
Patent foramen ovale closure (vs medical therapy)98
Recurrent ischaemic stroke 07% per year 13% per year 058 (034099)* 06%

TIA=transient ischaemic attack. NS=not signicant. ER=extended release. *Hazard ratio and 95% CI. Ipsilateral carotid-territory stroke from the end of the periprocedural period (30 days after completed
treatment). Odds ratio and 95% CI.

Table 4: Eect of secondary prevention strategies to prevent recurrent stroke

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extracranial to intracranial bypass surgery over medical
therapy for most patients with internal carotid artery
occlusion and severe haemodynamic impairment
because of the increased perioperative morbidity.109
Sustained lowering of blood pressure by 51 mm Hg
systolic and 25 mm Hg diastolic reduces recurrent
stroke by about a fth (table 4).93 More intensive blood
pressure lowering further reduces stroke risk.15 The
optimal target blood pressure is uncertain, but might be
120128 mm Hg systolic and 6570 mm Hg diastolic
after lacunar stroke.110 Visit-to-visit blood pressure
variability is reduced in a dose-dependent fashion by
calcium-channel blockers and diuretics, and increased by
blockers.111
Lowering of LDL cholesterol concentration by about
1 mmol/L with statins reduces the risk of recurrent
stroke by about 12%.94 More intensive lowering of LDL
cholesterol concentration is associated with further
reductions in stroke risk.16 The optimum target LDL
cholesterol concentration (259 mmol/L vs 18 mmol/L)
is being evaluated in the TST trial (appendix).
Long-term intensive glucose lowering does not reduce
non-fatal stroke risk compared with standard care in
patients with type 2 diabetes.112 Insulin sensitivity can be
improved by exercise, diet, weight reduction, and
peroxisome proliferator-activated receptor (PPAR-)
agonists. The PPAR- agonist, pioglitazone, reduces the
risk of recurrent stroke or myocardial infarction (table 4)21
but might increase the risk of bladder cancer, which
might preclude its use.113 Lowering homocysteine with
B vitamins has not been proven to signicantly reduce
the risk of recurrent stroke.114
Hormone therapy for post-menopausal women should
probably be stopped, if possible, as it increases the risk of
stroke by about a quarter.115 Regular physical activity,
low-risk diet (eg, Mediterranean diet), low alcohol
consumption, smoking cessation, avoidance of passive
smoking, and weight reduction, as appropriate, are
recommended. However, reliable evidence for their
ecacy to reduce recurrent stroke is not available.
Multimodal interventions that address lifestyle and
behaviour can improve drug compliance and reduce
blood pressure, but their eect on major vascular events
is not known.116,117
Preventing recurrent ischaemic stroke of cardiac
origin
In patients with atrial brillation, oral anticoagulation
with vitamin K antagonists, such as warfarin, to maintain
an INR of 2030, decreases the odds of recurrent
stroke by two-thirds.95 The four direct oral anticoagulants
that inhibit thrombin (dabigatran etexilate) and factor Xa
(rivaroxaban, apixaban, and edoxaban) reduce recurrent
stroke and systemic embolism by about a sixth, without
increasing major bleeding, compared to warfarin in non-
valvular atrial brillation.96 Dabigatran is not as eective
or safe as warfarin in patients with mechanical heart
8 www.thelancet.com Published online September 13, 2016 http://dx.doi.org/10.1016/S0140-6736(16)30962-X
valves.118 Selection of anticoagulant drugs is individualised
according to hepatic and renal function, potential for
drug interactions, patient preference, cost, tolerability,
and, among patients taking warfarin, time in the INR
therapeutic range.
The optimal time to start oral anticoagulation in acute
cardioembolic stroke is uncertain and the subject of
ongoing trials (appendix). However, it is probably
between 4 days and 14 days after stroke onset, depending
on the balance between the risk of recurrent stroke
(CHA2DS2-VASc score) and the risk of haemorrhagic
transformation of the infarcted brain (NIHSS and infarct
size).119 The longer-term risk of bleeding with
anticoagulation increases with higher HAS-BLED and
ABC bleeding scores (Age, Biomarkers [haemoglobin,
cTn-hs, and GDF-15 or cystatin C/CKD-EPI] and Clinical
history of previous bleeding]).120 For anticoagulated
patients who have serious bleeding or need an urgent
procedure, the anticoagulant eects of dabigatran can be
reversed rapidly by idarucizumab.62 Reversal agents for
Xa inhibitors in development include andexanet alfa, a
catalytically inactive recombinant human factor Xa
variant that competitively binds Xa inhibitors,63 and
ciraparantag (aripazine), a synthetic antidote to direct
thrombin and Xa inhibitors.64
If anticoagulation for atrial brillation is contraindicated,
left atrial appendage closure is an option given its comparable
ecacy to warfarin (table 4).97 The combination of clopidogrel
and aspirin is less eective than warfarin in patients with
atrial brillation but is more eective than aspirin.
Antiplatelet therapy and anticoagulation are associated
with similar rates of recurrent stroke in observational
studies of patients with cryptogenic stroke and patent
foramen ovale.121 Transcatheter-device patent foramen ovale
closure is associated with a marginally reduced rate of
recurrent ischaemic stroke compared with medical therapy
in patients with patent foramen ovale and cryptogenic
stroke or TIA but an increased risk of new-onset atrial
brillation.98 Ongoing trials are assessing the eectiveness
of antiplatelet therapy compared with patent foramen
ovale closure and compared with oral anticoagulants in
patients with patent foramen ovale-associated cryptogenic
stroke (appendix).
Recovery and rehabilitation
Patients with acute stroke need assessment for the nature
and severity of their neurological decits and the prognosis,
goals, and rehabilitation requirements for recovery. Stroke
rehabilitation is a progressive, dynamic, goal-orientated
process aimed at enabling a person with impairment to
reach their optimal physical, cognitive, emotional,
communicative, social, and functional activity level.122
Physical rehabilitation improves functional recovery
after stroke, and incorporates functional task training;
active and passive musculoskeletal, neurophysiological,
and cardiopulmonary intervention; and assistive devices
and modalities.123

Very early, high-intensity, and frequent mobilisation
has a less favourable outcome at 3 months after stroke
compared with usual care, particularly in patients with
intracerebral haemorrhage, suggesting that mobilisation
of patients in the rst 24 h after stroke should be cautious
and restricted to only a few times, each less than 10 min.124
Hand and arm function might be improved by
constraint-induced movement therapy, frequent
repetitive task practice, mental practice, mirror therapy,
interventions for sensory impairment, and virtual reality,
but the quality of the supporting evidence is only
moderate125 and the results not all favourable.126
Constraint-induced movement therapy involves
constraining the non-paretic arm (eg, wearing a mitt on
the non-paretic hand) and undertaking graded task-
oriented training of the paretic arm. Robot-assisted, task-
orientated, arm training devices could improve muscle
strength and function in the paretic arm, but the quality
of the evidence is low.127
Cardiorespiratory tness training that involves walking
improves balance and walking speed and capacity, but its
eect on death and dependence is uncertain.128 Treadmill
training, with or without bodyweight support using a
harness, might improve walking speed and walking
endurance in patients who are able to walk after stroke.129
For patients who cannot walk independently, robotic-
assisted gait training, combined with physical therapy,
might increase the odds of walking independently.129
Rhythmic auditory stimulation (ie, music therapy) could
also help to improve gait parameters in patients with
stroke.130
Intramuscular injection of botulinum toxin type A is
safe and reduces local muscle tone and pain due to
spasticity for up to 3 months after stroke. However,
whether it improves upper limb capacity or is cost-eective
is uncertain.131 Neuromuscular electric stimulation also
reduces spasticity and improves range of motion after
stroke.132
Speech and language therapy for post-stroke aphasia
improves functional communication compared with no
speech and language therapy, but not compared with social
support and stimulation.133 Transcranial direct-current
stimulation does not seem to improve post-stroke
functional communication, language impairment, or
cognition.134 Cognitive rehabilitation interventions have not
proved eective for reducing attentional impairments,
executive dysfunction, or spatial neglect.135137
There is insucient evidence for the ecacy of any
intervention to treat or prevent fatigue after stroke.138
Small trials suggest that neurotrophic drugs, such as
cerebrolysin and selective serotonin-reuptake inhibitors,
might improve neurological recovery from stroke but
the results are inconclusive and subject to evaluation in
ongoing trials (appendix).139 Preliminary evidence
supports the feasibility, tolerability and safety of
intravenous transplantation of autologous bone marrow
mononuclear cells in patients with subacute (730 days)
www.thelancet.com Published online September 13, 2016 http://dx.doi.org/10.1016/S0140-6736(16)30962-X
Seminar
stroke140 and stereotactic intracerebral transplantation of
human neural stems cells in patients with chronic
(660 months) stroke.141 Stem-cell therapy aims to
protect subacutely ischaemic and surrounding brain by
suppressing inammation and apoptosis, and to repair
and regenerate chronically damaged brain by
stimulating growth factor secretion, cell replacement,
and biobridge formation.
Early supported discharge services that are
appropriately resourced and have a coordinated team
can reduce length of hospital stay, admission to
institutional care, and long-term dependency in elderly
stroke patients with mild to moderate disability without
adversely aecting the mood or subjective health status
of patients or carers.142 Stroke survivors and their
caregivers should be encouraged to join their local stroke
support organisation. Support and advice from
organisations and from other stroke patients and their
family can reduce social isolation and depression and
improve quality of life.
Interventions under investigation and future
directions
Several promising interventions are undergoing evaluation
(appendix). The initial management of acute stroke is
being extended from hospital emergency departments to
ambulances where opportunities exist to intervene in the
rstso-called goldenhour. Ambulance-based
interventions undergoing evaluation include stroke
assessment tools for paramedics to reliably identify
patients with large artery occlusion, ambulance-based
mobile brain imaging and point-of-care laboratory tests to
distinguish haemorrhagic from ischaemic stroke,
telemedicine communication with the admitting
emergency department or stroke team, stroke care
algorithms, altering head position to optimise brain
perfusion, lowering blood pressure to prevent haematoma
expansion, lowering body temperature to protect ischaemic
brain tissue, starting neuroprotective and anti-
inammatory drugs, and starting intravenous thrombolysis
or haemostatic therapy in appropriate patients.
Ongoing trials are investigating strategies to improve
the safety of thrombolysis (eg, by lowering blood pressure
and using specic antidotes for patients taking direct oral
anticoagulants), to improve the ecacy of thrombolysis
(eg, by combining thrombolysis with neuroprotective
and anti-inammatory therapies such as uric acid,
minocycline, ngolimod, natalizumab, growth factors,
and hypothermia), to identify more eective thrombolytic
drugs (eg, tenecteplase), and to determine the brain
imaging and threshold measures of volume of core
infarction and penumbral mismatch (ratio of ischaemic
tissue at risk to core infarction) that might optimise
patient selection and extend the time window for eective
reperfusion therapy.
The evidence base for eective mechanical
thrombectomy has so far been derived from experienced,
9
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comprehensive stroke centres; therefore, registry studies
are planned in less experienced centres to verify
generalisability and external validity. The eect of
endovascular thrombectomy also awaits investigation in
patients with mild ischaemic stroke (eg, NIHSS
score <10), basilar artery occlusion, or distal occlusions of
the M2 middle cerebral artery segment, as does the
optimum treatment for patients with concomitant
(tandem) occlusion of the extracranial internal carotid
artery. It is also uncertain whether proceeding directly to
thrombectomy, and withholding alteplase in alteplase-
eligible patients, in patients with large artery occlusion
will improve safety and ecacy compared with the
current approach of combined alteplase and endovascular
therapy. Eorts are ongoing to improve the technological
aspects of mechanical thrombectomy to further reduce
procedural time, increase the rate of complete
reperfusion, and minimise harm.
Ongoing studies in acute haemorrhagic stroke promise
to provide evidence of the clinical eectiveness of
prehospital blood pressure lowering, neuroprotection
and anti-inammation (eg, ngolimod), non-specic
haemostatic and antibrinolytic therapies, specic
antidotes to direct oral anticoagulants, and minimally
invasive surgery via burr hole combined with local
thrombolysis.
To prevent recurrent atherothrombotic ischaemic stroke,
trials are in progress or being planned to assess the
incremental benet of adding aspirin to clopidogrel,
cilostazol, a potent selective protease-activated
receptor 4 (PAR4) antagonist, ticagrelor, rivaroxaban, or
the combination of clopidogrel and dipyridamole. Trials
of drugs that inactivate proprotein convertase
subtilisin/kexin type 9 (PCSK9) by means of humanised
monoclonal anti-PCSK9 antibodies, and lower
LDL-cholesterol concentrations by at least 50%, are awaited
in patients with ischaemic stroke. Cerebral small-vessel
disease might be prevented by interventions that target
brain microvascular endothelium and the bloodbrain
barrier, microvascular function, and neuroinammation.
To prevent embolic stroke of uncertain source, three
trials are evaluating the eect of the direct oral
anticoagulants rivaroxaban, dabigatran, and apixaban,
compared with aspirin. To prevent ischaemic events after
intracerebral haemorrhage, the safety and eectiveness of
starting or restarting antithrombotic treatment is being
addressed in ongoing trials. Other potential new strategies
of stroke prevention that are being evaluated include
ischaemic preconditioning and treating obstructive sleep
apnoea with continuous positive airway pressure.
High-quality randomised controlled trials are needed
to establish the observed benets of constraint-induced
movement therapy, mental practice, mirror therapy,
virtual reality and interactive video gaming, and relatively
intense repetitive task practice.
Trials are also needed to provide more reliable estimates
of the eects of repetitive transcranial magnetic
10 www.thelancet.com Published online September 13, 2016 http://dx.doi.org/10.1016/S0140-6736(16)30962-X
stimulation, transcranial direct-current stimulation,
acupuncture, vagus nerve stimulation paired with upper-
limb rehabilitation, intensive aphasia therapy, hands-on
therapy, music therapy, interventions for sensory
impairment, pharmacological interventions for recovery
such as cerebrolysin and uoxetine, and intrastriatal
injection of allogeneic human neural stem cells.
Because most strokes occur in LMICs where access to
stroke units and rehabilitation is poor, a trial in India is
examining whether rehabilitation in the home by a
trained family member is eective and aordable for
patients with recent disabling stroke, compared with
usual care.
Conclusion
The past decade has seen extraordinary advances in the
treatment and prevention of stroke. The most exciting
has been the dramatic eect of endovascular
thrombectomy in reducing death and dependency
for an additional one in ve patients with acute large
vessel ischaemic stroke. This advance reects a dedicated
commitment to harmoniously integrating ecient,
expert multidisciplinary systems of stroke care with
advances in brain imaging and stent-retriever technology.
The ndings present implementation challenges for
stroke networks. Also salutary are the lower rates of
recurrent stroke in the past decade. The magnitude and
nature of the early benets of immediate aspirin for TIA
and ischaemic stroke are now recognised. Intensive and
sustained reductions in blood pressure and cholesterol
and carotid revascularisation for select patients with
symptomatic carotid stenosis are associated with rates of
less than 1% per year of post-procedural recurrent
ipsilateral stroke at 5 years after carotid endarterectomy
or stenting; several-times lower than rates for similar
patients treated medically 25 years ago (table 4).8487
Recent evidence indicates that treating insulin resistance
also prevents recurrent vascular events. The advent of
direct oral anticoagulants has increased the uptake of
eective anticoagulant thromboprophylaxis among
patients with atrial brillation at high risk of recurrent
cardioembolic stroke. However, despite these advances,
the global burden of stroke remains substantial and is
increasing as populations age. There is no country in
which the number of people aected by stroke has
decreased in the past two decades. The burden of stroke
is also increasing among young adults and is greatest in
developing countries. An improved understanding of,
and commitment to, the disparities in stroke burden
trends and access to appropriate and aordable stroke
care between countries and regions of dierent income
levels is needed to address the increasing global burden
of stroke.
Declaration of interests
I have received honoraria from AC Immune for chairing the data safety
monitoring committee of two clinical trials of vaccines for Alzheimers
disease, from Bayer for lecturing about stroke prevention in atrial

brillation at sponsored scientic symposia, and from Medscape,
Web MD, for participating in a discussion about stroke prevention in
atrial brillation for theheart.org.
Acknowledgments
I thank Jerey L Saver (University of California, Los Angeles, USA)
for helpful comments and suggestions regarding the manuscript.
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