addition of endovascular thrombectomy

www.thelancet.com Vol 389 February 11, 2017 641
Seminar
Stroke
Graeme J Hankey
In the past decade, the defi nition of stroke has been revised and major advances have been made for its treatment and
prevention. For acute ischaemic stroke, the addition of endovascular thrombectomy of proximal large artery occlusion
to intravenous alteplase increases functional independence for a further fi fth of patients. The benefi ts of aspirin in
preventing early recurrent ischaemic stroke are greater than previously recognised. Other strategies to prevent recurrent
stroke now include direct oral anticoagulants as an alternative to warfarin for atrial fi brillation, and carotid stenting as
an alternative to endarterectomy for symptomatic carotid stenosis. For acute intracerebral haemorrhage, trials are
ongoing to assess the eff ectiveness of acute blood pressure lowering, haemostatic therapy, minimally invasive surgery,
anti-inflammation therapy, and neuroprotection methods. Pharmacological and stem-cell therapies promise to facilitate
brain regeneration, rehabilitation, and functional recovery. Despite declining stroke mortality rates, the global burden of
stroke is increasing. A more comprehensive approach to primary prevention of stroke is required that targets people at
all levels of risk and is integrated with prevention strategies for other diseases that share common risk factors.
Introduction
The world is facing an epidemic of stroke. Despite stable
incidence rates and declining mortality rates over the past
two decades, the number of incident strokes, prevalent
stroke survivors, disability-adjusted life-years (DALYs) lost
due to stroke, and stroke-related deaths is increasing.1 This
Seminar highlights recent developments in the definition,
treatment, and prevention of stroke to help clinicians to
manage stroke and reduce its impact on affected
individuals, their carers, and the population as a whole.
Epidemiology
In 2010, an estimated 16·9 million incident strokes
occurred, which added to a pool of 33 million stroke
survivors worldwide (table 1).1 There were 5·9 million
deaths and 102 million DALYs lost due to stroke, making
stroke the second leading cause of death after ischaemic
heart disease and third leading cause of DALYs lost
worldwide. Most of the global burden of stroke, in terms
of deaths and DALYs lost, was borne by low-income and
middle-income countries (LMICs) and caused by
haemorrhagic stroke.2
Between 1990 and 2010, the global incidence rate of
stroke remained stable but the number of incident first
strokes increased by 68%. The prevalence of stroke
increased slightly, yet the number of stroke survivors
increased by 84%. The number of DALYs lost per stroke
decreased, but the total number of DALYs lost increased
by 12%. The mortality rate fell, but the number of
stroke-related deaths increased by 26% (table 1).1 The
reduction in rates can probably be attributed to improved
prevention and management of stroke, particularly in
high-income countries. The increase in numbers, despite
reductions in rates, probably refl ects global population
growth, increasing life expectancy, and a change in the
age structure of most populations.
Definition of stroke and transient ischaemic attack
The traditional definition of stroke is clinical and based
on the sudden onset of loss of focal neurological function
due to infarction or haemorrhage in the relevant part of
the brain, retina, or spinal cord. Stroke is distinguished
from transient ischaemic attack (TIA) if the symptoms
persist longer than 24 h (or lead to earlier death). An
updated defi nition of stroke is an acute episode of focal
dysfunction of the brain, retina, or spinal cord lasting
longer than 24 h, or of any duration if imaging (CT or
MRI) or autopsy show focal infarction or haemorrhage
relevant to the symptoms.3 The definition includes
subarachnoid haemorrhage.3 A TIA has been redefined
as focal dysfunction of less than 24 h duration and with
no imaging evidence of infarction.3
Diagnosis of stroke
Typical symptoms of stroke include sudden unilateral
weakness, numbness, or visual loss; diplopia; altered
speech; ataxia; and non-orthostatic vertigo.4 Associated
symptoms (eg, headache) vary and usually reflect the
cause or consequences of the stroke. Atypical symptoms
of stroke include isolated vertigo, binocular blindness,
amnesia, anosognosia, dysarthria, dysphagia, stridor,
foreign accent, or headache; hemiballismus; alien hand
syndrome; confusion; and altered consciousness.4
Diagnostically, the Face Arm and Speech Test (FAST)
aids screening for stroke and is as sensitive and specific
as the Recognition of Stroke in the Emergency Room
(ROSIER) score.4,5 Non-contrast cranial CT scan has
near-perfect sensitivity to detect fresh intracranial
haemorrhage, but its sensitivity for diagnosis of
ischaemic stroke is poor if ischaemia is recent, small, or
in the posterior fossa. Diffusion weighted MRI
Lancet 2017; 389: 641–54
Published Online
September 13, 2016
http://dx.doi.org/10.1016/
S0140-6736(16)30962-X
School of Medicine &
Pharmacology, The University
of Western Australia, Perth,
WA, Australia
(Prof G J Hankey MD);
Department of Neurology,
Sir Charles Gairdner Hospital,
Perth, WA, Australia
(Prof G J Hankey); and Western
Australian
Neuroscience Research
Institute (WANRI), Perth, WA,
Australia (Prof G J Hankey)
Correspondence to:
Prof Graeme J Hankey, School of
Medicine and Pharmacology,
The University of Western
Australia, Perkins Institute of
Medical Research, QEII Medical
Centre, Perth, WA 6009,
Australia
graeme.hankey@uwa.edu.au
Search strategy and selection criteria
I searched the Cochrane Library, PubMed, and MEDLINE using
the search term “stroke” in combination with the terms
“diagnosis”, “risk factors”, “prognosis”, “treatment”, and
“prevention” for articles published between Jan 1, 2010, and
June 1, 2016. I also searched the reference lists of articles
identifi ed by the search. I selected mainly articles published in
the past 5 years, but included older key publications.
Seminar
642 www.thelancet.com Vol 389 February 11, 2017
(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 20–25% 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 diffi cult 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 diff erent 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 classifi ed according to the TOAST
classification,10 the ASCOD phenotyping system
(A: atherosclerosis; S: small-vessel disease; C: cardiac
pathology; O: other cause; D: dissection),11 and the
Causative Classification System.12 A third of ischaemic
strokes remain of undetermined cause (ie, cryptogenic),
of which a subgroup is now defi ned as having embolic
strokes of undetermined source.13
Haemorrhagic stroke is classifi ed according to its
anatomical site or presumed aetiology. The most
common sites of intracerebral haemorrhage are
supratentorial (85–95%), including deep (50–75%) and
lobar (25–40%).14 The most common causes are
hypertension (30–60%), cerebral amyloid angiopathy
(10–30%), anticoagulation (1–20%), and vascular
structural lesions (3–8%); the cause is undetermined in
about 5–20% of cases.14
Risk factors
Hypertension, hypercholesterolaemia, carotid stenosis,
and atrial fi 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.15–18 Cigarette smoking, excessive alcohol use,
insulin resistance, and diabetes mellitus are also likely
causal risk factors.19–22 Other risk factors that, if modified,
could reduce the incidence of stroke include
environmental air pollution, childhood health
circumstances and fitness, high-risk diet and poor
nutrition, physical inactivity, obesity, blood pressure
variability, sleep-disordered breathing, chronic inflammation, 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 subtypes—eg, the ZFHX3
1990 2005 2010 Change from 1990–2010
Number of
events
Rate per 100 000
person-years
Number of
events
Rate per 100 000
person-years
Number of
events
Rate per 100 000
person-years
Change in
number of
events
Change in rate in HICs Change in rate in LMICs
All stroke

··
··
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
Seminar
www.thelancet.com Vol 389 February 11, 2017 643
gene on chromosome 16q22 and PITX2 gene on
chromosome 4q25 for cardioembolic stroke; the HDAC9
gene on chromosome 7p21 and locus on chromosome
1p13.2 near the TSPAN2 gene for large-vessel stroke; and
chromosome 6p25 near the FOXF2 gene for small-vessel
disease.25,26 Genetic variants ε2 and ε4 within the
apolipoprotein E (APOE) gene are risk factors for lobar
intracerebral haemorrhage.
Ten treatable risk factors account for about 90% of the
population-attributable risk of stroke.23,24 Stroke can also be
triggered by several activities (eg, neck trauma and coitus)
and risk factors (eg, alcohol, amphetamines, infection, and
air pollution, and perhaps psychosocial stress).27
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 (modifi ed Rankin Scale
[mRS] score 3–5) between 1 month and 5 years after
stroke; 20% are disabled before the stroke.28Five 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 atherosclerosis and high ABCD³-I and recurrence risk estimator
scores (table 2);32,33 the ABCD² 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 fi 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 highsensitivity (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 1·3% to
7·4%.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 prespecified
limits.39
Specific treatment for acute ischaemic stroke
Intravenous alteplase (rtPA), 0·9 mg/kg, administered
within 4·5 h of ischaemic stroke, increases the odds of
no signifi cant disability (mRS 0–1) at 3–6 months by
about a third and does not aff ect mortality, despite
increasing the odds of symptomatic intracerebral
haemorrhage (table 3).40 The proportional benefits 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 (0·6 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
Score for
characteristic
ABCD³-I score32*
Age ≥60 years 1
Blood pressure ≥140/90 mm Hg 1
Clinical features
Speech impairment without weakness 1
Unilateral weakness 2
Duration
10–59 min 1
≥60 min 2
Diabetes mellitus present 1
Dual TIA (index TIA plus ≥1 other TIA in preceding 7 days) 2
Imaging: ipsilateral ≥50% stenosis of internal carotid
artery
2
Imaging: acute diffusion-weighted imaging
hyperintensity
2
Recurrence risk estimator at 90 days33†‡
Clinical
History of TIA or stroke within the preceding month of
index stroke
1
CCS aetiological stroke subtype
Large artery atherosclerosis 1

If the stated criteria are not met, a score of 0 is assigned. NA=not applicable.
TIA=transient ischaemic attack. CCS=Causative Classifi cation System for Ischemic
Stroke. *Total range 0–13. †Total range 0–6. ‡Available at: http://www.nmr.mgh.
harvard.edu/RRE-90.
Table 2: Scores to identify patients at early risk of recurrent stroke32,33
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644 www.thelancet.com Vol 389 February 11, 2017
doppler ultrasound,51 hypothermia,52 or desmoteplase.53
Tenecteplase is being compared with alteplase in several
phase 3 trials (appendix).54 Concomitant antithrombotic
drugs should be avoided for the fi rst 24 h after alteplase to
limit haemorrhagic transformation of any infarcted brain.55
The addition of endovascular thrombectomy with
second-generation devices (eg, stent retrievers) to
alteplase within 6 h of ischaemic stroke doubles the rate
of angiographic revascularisation at 24 h and functional
independence at 90 days (table 3), and increases the
likelihood of improving by 1 point or more on the mRS
by 2·5 times, without increasing risk of symptomatic
intracerebral haemorrhage or all-cause mortality.41,42 The
effect is consistent among elderly people (>80 years) and
patients ineligible for intravenous alteplase.
Improved outcomes with endovascular thrombectomy
in recent trials can be attributed to improved patient
selection by CT or MR angiogram to confi rm large artery
occlusion (figure), shorter time to revascularisation, and
second-generation devices and techniques that enable
higher rates of reperfusion.41,42,56 Ongoing trials are
evaluating whether patients with small ischaemic cores
and substantial salvageable penumbra, as identified by
CT or MR perfusion, could benefit from alteplase and
endovascular thrombectomy beyond 6 h (appendix).56
Implementation of endovascular therapy in clinical
practice will require local algorithms to enable emergency
medical services to rapidly and accurately identify, triage,
and transport the 10% of stroke patients suitable for
endovascular therapy directly to comprehensive stroke
centres where resourced, accessible, and specialised stroke
teams can restore reperfusion within 90 min of arrival.57
Specifi c treatment for acute haemorrhagic
stroke
Intensive blood pressure reduction within 3–6 h of onset
of intracerebral haemorrhage to a systolic target of lower
than 140 mm Hg may not be safe for all patients, nor more
effective in reducing death and disability, compared to a
systolic target of lower than 180 mm Hg (table 3).45,46
For intracerebral haemorrhage not associated with
antithrombotic therapy, recombinant activated factor
VII (rFVIIa) decreases haematoma growth, but increases
thromboembolic events, and does not improve functional
outcome.58 Platelet transfusion after intracerebral
haemorrhage associated with antiplatelet drugs increases
death and dependence at 3 months.59 For spontaneous
intracerebral haemorrhage associated with vitamin K
antagonist anticoagulation, reversal of the INR to lower
than 1·3 and reduction of the systolic blood pressure to
lower than 160 mm Hg within 4 h is associated with
reduced hematoma enlargement.60 Four-factor
prothrombin complex concentrate seems superior to fresh
frozen plasma to normalise the INR and reduce
haematoma expansion.61 Management of acute
intracerebral haemorrhage associated with direct
inhibition of thrombin or factor Xa by direct oral
anticoagulants requires immediate cessation of the direct
oral anticoagulants, supportive measures, and
consideration of specifi c reversal agents, such as
idarucizumab for dabigatran-associated intracerebral
haemorrhage, or non-specifi c haemostatic agents, such as
prothrombin complex concentrate, that show positive
laboratory results.61–65
Proportion of patients
with reported functional
outcome
Odds ratio
(95% CI)
Absolute
difference
(%)
Treatment
group (%)
Control
group (%)
Ischaemic stroke
Thrombolysis with alteplase40
Good recovery (mRS 0–1) in patients
who received alteplase 0–4·5 h after
stroke
34% 28% 1·37 (1·20–1·56) 7%
Good recovery (mRS 0–1) in patients
who received alteplase 0–3 h after
stroke
33% 23% 1·75 (1·35–2·27) 10%
Good recovery (mRS 0–1) in patients
who received alteplase 3–4·5 h after
stroke
35% 30% 1·26 (1·05–1·51) 6%

<180 mm Hg)45,46

Endovascular thrombectomy given plus thrombolysis and usual care in most participants. mRS=modifi ed Rankin Scale
score. ICH=intracerebral haemorrhage. NS=not signifi cant. BP=blood pressure. *Risk ratio (95% CI).
Table 3: Eff ect of treatments or care strategies for ischaemic stroke, intracerebral haemorrhage, or all
stroke on functional outcome
See Online for appendix
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www.thelancet.com Vol 389 February 11, 2017 645
Early open-surgery evacuation of supratentorial
haematomas might be benefi cial for patients with a
Glasgow Coma Scale score of 9–12 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 fibrinolysis 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 30–40 mm, haematoma volume
higher than 7 cm³, 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 fluids and nutrition in the fi 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 fl uid delivery for
patients with poor oral fl uid intake. Hypertonic fluids
(colloids) increase pulmonary oedema compared with
isotonic fluids (crystalloids).71For patients with dysphagia,
the effect of various swallowing therapies, feeding, and
nutritional and fluid 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 benefit 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).
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 filling 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 fl 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 fl 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 fl 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
fi 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 fl 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).
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646 www.thelancet.com Vol 389 February 11, 2017
Lowering blood pressure during the fi rst days after
major stroke does not improve functional outcome.74,75
There is no urgency to restart pre-existing antihypertensive therapy in the fi 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 4·0–7·5 mmol/L in the first
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 4–7 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 ineff ective. The benefi ts of low-dose
subcutaneous heparins and heparinoids in reducing
venous thromboembolism are off set 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 signifi cantly decreases 12 month mortality,
death or severe disability (mRS score >4), and death or
major disability (mRS score >3), but is associated with
non-significantly higher major disability (mRS
score 4–5) among survivors compared with conservative
treatment (table 3).44 The trade-off 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 undefi ned. 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 eff ective secondary prevention after
TIA and minor ischaemic stroke can reduce the risk of
early recurrent stroke by 80% (table 4).35 Immediate
aspirin, 160–300 mg a day, reduces the rate and severity
of early recurrent stroke by at least half within the first
6–12 weeks (table 4).43,81 Ticagrelor is as safe as aspirin in
patients with acute TIA and mild ischaemic stroke, but is
not superior to aspirin in reducing the 90 day rate of
stroke, myocardial infarction, or death.82
Dual antiplatelet therapy seems more effective than
monotherapy in reducing early recurrent stroke
(table 4).83 The most eff ective 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).
Effective long-term antiplatelet regimens for preventing
recurrent stroke include aspirin 75–150 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).88–92 Long-term triflusal, terutroban,
vitamin K antagonists, aspirin plus clopidogrel, and
vorapaxar plus standard antiplatelet treatment are not as
safe and eff ective 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
effective 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 70–99% stenosis, and a quarter with 50–69%
stenosis, when added to medical therapy 25 years ago
(table 4).84,104 The second ECST-2 trial is currently comparing
the risks and benefi ts 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 differences 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).85–87 If carotid revascularisation is to be done, it
should be early, within the fi 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.106–108 There is also no benefi t of flow-augmentation
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www.thelancet.com Vol 389 February 11, 2017 647
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% 0·20 (0·08–0·49) 12%
Aspirin (vs control)43,81
Stroke at 6 weeks 1% 2% 0·45 (0·35–0·58) 1·3%
Stroke at 12 weeks 2% 4% 0·49 (0·40–0·60)* 1·8%
Disabling or fatal ischaemic stroke at 12 weeks 1% 2% 0·34 (0·25–0·46)* 1·4%
Ticagrelor (vs aspirin)82
Stroke at 90 days 6% 7% 0·86 (0·75–0·99)* 0·9%
Dual antiplatelet therapy (vs single drug)83
Stroke at about 90 days 6% 9% 0·69 (0·60–0·80) 2·8%
Carotid endarterectomy (vs medical therapy)84
Any stroke or operative death at 5 years in patients with 70–99% carotid stenosis 15% 29% 0·53 (0·42–0·67) 13·9%
Any stroke or operative death at 5 years in patients with 50–69% carotid stenosis 17% 23% 0·77 (0·63–0·94) 5·6%
Ipsilateral ischaemic stroke and any operative stroke or death at 5 years in patients with 70–99% carotid stenosis 10% 24% 0·40 (0·30–0·54) 14·2%
Ipsilateral ischaemic stroke and any operative stroke or death at 5 years in patients with 50–69% carotid stenosis 12% 15% 0·82 (0·64–1·05) NS; p=0·11
Carotid stent (vs carotid endarterectomy)85–87
Any stroke or death85 25% 21% 1·41 (1·07–1·84) 4·3%
Any stroke at 5 years86 15% 9% 1·71 (1·28–2·30)* 5·8%
Fatal or disabling stroke at 5 years86 6% 6% 1·06 (0·72–1·57)* NS; p=0·77
Ipsilateral carotid stroke at 5 years†86 5% 3% 1·29 (0·74–2·24) NS; p=0·36
Longer-term therapy in patients with TIA or ischaemic stroke
Aspirin88
Stroke per year 4% 5% 0·83 (0·72–0·96) 0·8%
Clopidogrel (vs aspirin)89
Recurrent stroke at 2 years 11% 12% 0·90 (0·80–1·00)‡ 1%
Aspirin plus ER dipyridamole (vs aspirin)90
Recurrent stroke at 2·6 years 9% 11% 0·78 (0·68–0·90)* 2·3%
Aspirin plus ER dipyridamole (vs clopidogrel)91
Recurrent stroke at 2·5 years 9% 9% 1·01 (0·92–1·11)* NS; p=0·71
Cilostazol (vs aspirin)92
Recurrent stroke at 3 years 5% 8% 0·67 (0·52–0·86) 2·7%
Blood pressure lowering by 5·1/2·5 mm Hg93
Recurrent stroke at 3 years 9% 10% 0·78 (0·68–0·90) ‡ 1·3%
LDL cholesterol lowering by 1 mmol/L94
Recurrent stroke at 5 years 11% 12% 0·88 (0·78–0·99) 1·4%
Pioglitazone for insulin resistance21
Stroke or myocardial infarction 9% 12% 0·76 (0·62–0·93)* 2·8%
Recurrent stroke at 4·8 years 7% 8% 0·82 (0·61–1·10)* NS; p=0·19
Warfarin for atrial fibrillation (vs control)95
Recurrent stroke at 2 years 9% 23% 0·36 (0·22–0·58)‡ 14%
Direct oral anticoagulants (vs warfarin)96
Stroke or systemic embolism at 2 years 5% 6% 0·86 (0·76–0·98) 0·8%
Left atrial appendage closure (vs warfarin)97
Stroke or systemic embolism at 2·7 years 1·75% per year 1·87% per year 1·02 (0·62–1·7)* NS; p=0·94
Patent foramen ovale closure (vs medical therapy)98
Recurrent ischaemic stroke 0·7% per year 1·3% per year 0·58 (0·34–0·99)* 0·6%
TIA=transient ischaemic attack. NS=not signifi cant. 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: Effect 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 5·1 mm Hg
systolic and 2·5 mm Hg diastolic reduces recurrent
stroke by about a fi fth (table 4).93 More intensive blood
pressure lowering further reduces stroke risk.15 The
optimal target blood pressure is uncertain, but might be
120–128 mm Hg systolic and 65–70 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
β 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 (2·59 mmol/L vs 1·8 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 γ (PPAR-γ)
agonists. The PPAR-γ 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 significantly 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
efficacy to reduce recurrent stroke is not available.
Multimodal interventions that address lifestyle and
behaviour can improve drug compliance and reduce
blood pressure, but their eff ect on major vascular events
is not known.116,117
Preventing recurrent ischaemic stroke of cardiac
origin
In patients with atrial fibrillation, oral anticoagulation
with vitamin K antagonists, such as warfarin, to maintain
an INR of 2·0–3·0, 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 nonvalvular atrial fibrillation.96 Dabigatran is not as effective
or safe as warfarin in patients with mechanical heart
valves.118Selection 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 eff ects 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 fi brillation is contraindicated,
left atrial appendage closure is an option given its comparable
efficacy to warfarin (table 4).97 The combination of clopidogrel
and aspirin is less eff ective than warfarin in patients with
atrial fi brillation but is more eff ective 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.121Transcatheter-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
fibrillation.98 Ongoing trials are assessing the effectiveness
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 defi cits 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
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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 fi 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 taskoriented training of the paretic arm. Robot-assisted, taskorientated, arm training devices could improve muscle
strength and function in the paretic arm, but the quality
of the evidence is low.127
Cardiorespiratory fitness training that involves walking
improves balance and walking speed and capacity, but its
effect on death and dependence is uncertain.128Treadmill
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, roboticassisted 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-effective
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.134Cognitive rehabilitation interventions have not
proved eff ective for reducing attentional impairments,
executive dysfunction, or spatial neglect.135–137
There is insuffi cient evidence for the efficacy 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 (7–30 days)
stroke140 and stereotactic intracerebral transplantation of
human neural stems cells in patients with chronic
(6–60 months) stroke.141 Stem-cell therapy aims to
protect subacutely ischaemic and surrounding brain by
suppressing infl ammation 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 affecting 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 fi rst—so-called golden—hour. 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-infl ammatory 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 specifi c antidotes for patients taking direct oral
anticoagulants), to improve the efficacy of thrombolysis
(eg, by combining thrombolysis with neuroprotective
and anti-inflammatory therapies such as uric acid,
minocycline, fingolimod, natalizumab, growth factors,
and hypothermia), to identify more effective 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 effective
reperfusion therapy.
The evidence base for effective mechanical
thrombectomy has so far been derived from experienced,
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650 www.thelancet.com Vol 389 February 11, 2017
comprehensive stroke centres; therefore, registry studies
are planned in less experienced centres to verify
generalisability and external validity. The effect 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 alteplaseeligible patients, in patients with large artery occlusion
will improve safety and effi cacy compared with the
current approach of combined alteplase and endovascular
therapy. Eff orts 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 effectiveness of
prehospital blood pressure lowering, neuroprotection
and anti-infl ammation (eg, fingolimod), non-specifi c
haemostatic and antifibrinolytic therapies, specific
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 benefi t 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 blood–brain
barrier, microvascular function, and neuroinflammation.
To prevent embolic stroke of uncertain source, three
trials are evaluating the effect of the direct oral
anticoagulants rivaroxaban, dabigatran, and apixaban,
compared with aspirin. To prevent ischaemic events after
intracerebral haemorrhage, the safety and effectiveness 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 benefi ts 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 eff ects of repetitive transcranial magnetic
stimulation, transcranial direct-current stimulation,
acupuncture, vagus nerve stimulation paired with upperlimb rehabilitation, intensive aphasia therapy, hands-on
therapy, music therapy, interventions for sensory
impairment, pharmacological interventions for recovery
such as cerebrolysin and fl 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 effective and affordable 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 effect of endovascular
thrombectomy in reducing death and dependency
for an additional one in five patients with acute large
vessel ischaemic stroke. This advance reflects a dedicated
commitment to harmoniously integrating efficient,
expert multidisciplinary systems of stroke care with
advances in brain imaging and stent-retriever technology.
The findings 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 benefits 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).84–87
Recent evidence indicates that treating insulin resistance
also prevents recurrent vascular events. The advent of
direct oral anticoagulants has increased the uptake of
effective anticoagulant thromboprophylaxis among
patients with atrial fibrillation 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 affected 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 affordable stroke
care between countries and regions of different 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 Alzheimer’s
disease, from Bayer for lecturing about stroke prevention in atrial
Seminar
www.thelancet.com Vol 389 February 11, 2017 651
fi brillation at sponsored scientifi c symposia, and from Medscape,
Web MD, for participating in a discussion about stroke prevention in
atrial fi brillation for theheart.org.
Acknowledgments
I thank Jeff rey L Saver (University of California, Los Angeles, USA)
for helpful comments and suggestions regarding the manuscript.
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