6.

6: Acute Stroke

Priority Medicines for Europe and the World

"A Public Health Approach to Innovation"

Background Paper

Acute Stroke

By Dr Eduardo Sabat and Dr Sunil Wimalaratna

With appreciation to the WHO/CVD Unit and Drs Julien.Bogousslavsky, Patrik Michel, and
Cesare Fieschi for their comments.

7 October 2004

6.6-1

6.6: Acute Stroke

Table of Contents
Abbreviations.........................................................................................................................................3
Summary.................................................................................................................................................4
6.6.1

Introduction...............................................................................................................................5

6.6.2

Burden of stroke........................................................................................................................8

6.6.3

Control strategy.......................................................................................................................12

6.6.4

Major problem and challenges of stroke management: why does the disease burden
persist?......................................................................................................................................14

6.6.5

Past and current research into pharmaceutical interventions for managing stroke........15

6.6.6

What are the opportunities for research into new pharmaceutical interventions that
might fill the current gap and make a substantial difference?...........................................18

6.6.7

Conclusions..............................................................................................................................20

6.6.8

References................................................................................................................................21

6.6-2

6.6: Acute Stroke

Abbreviations

COPD: Chronic Obstructive Pulmonary

Diseases

LBW: low birth weight

LRI: Low Respiratory Infections
MRI: magnetic resonance imaging

CT: computerized tomography

NIHSS: National Institutes of Health Stroke

Scale

CVA: cerebrovascular accident

DALY: disability-adjusted life years

NINDS: National Institute of Neurologic

Diseases Study

DWI: Diffusion-weighted imaging

EU: European Union

ODD, other digestive diseases

EU10: European Unions new accession

countries.

OID, other infectious diseases

OUI: other unintentional injuries

EU15: European Union with 15 countries

QALY: Quality-adjusted Life Years

EU25: European Union with 25 countries

rt-PA: recombinant tissue plasminogen

activator

FDA: Food and Drug Administration

HL, hearing loss, adult onset

TBLC, trachea, bronchus, lung cancers

IHD: Ischaemic Heart Disease

TIA: transient ischaemic attacks

6.6-3

6.6: Acute Stroke

Summary
Stroke is an abrupt onset of a focal neurological deficit secondary to a vascular event lasting
more than 24 hours. An acute stroke refers to the first 24-hour-period of a stroke event. Stroke
is classified as either ischaemic (caused by thrombosis or embolisms) or haemorrhagic (caused
mainly by rupture of blood vessel or aneurysm).
The occlusion of the cerebral artery causes decreased blood flow and ischaemia. Depending on
the severity of the ischemia, infarction (cellular death) will occur within minutes, causing
irreversible damage even after blood flow is restored. This is called the core of the infarct.
Surrounding the core is tissue that is affected but functionally that may recover if blood flow is
restored. This is called the ischaemic penumbra. Most people will have such an ischaemic
penumbra amenable to treatment within the first 3 hours of occlusion of the cerebral artery,
but many patients may have it up to 12 hours. This is the so-called therapeutic window.
Thus proper identification of treatable patients is crucial for the efficacy of the interventions.
Stroke is the second leading cause of death worldwide and in the European region. Ten per
cent of the 55 million deaths that occur every year worldwide are due to stroke. The overall
mortality from stroke has been declining both worldwide and in Europe. This is mainly due to
improved access to appropriate health care, with the consequent rise in health care costs. In
Europe, discharges following hospitalization for stroke doubled during the last 15 years of the
twentieth century. The United Kingdom spends 6% of its national health budget on stroke
care, twice as much spent on ischaemic heart disease (IHD).
The successful management of acute stroke is based on imaging followed by two main
strategies: vascular recanalization and supportive care. Differential diagnosis with
haemorrhagic stroke is important. Restoration or improvement of perfusion to the ischaemic
area is a key therapeutic strategy. However, currently available options, aspirin (1% better than
placebo) and recombinant tissue plasminogen activator (rt-PA) (10% better than placebo) are
not very effective. Current stroke therapy, therefore, is mainly based on general care and
rehabilitation.
In most patients who have had a haemorrhagic stroke, current treatment focuses on evacuation
of the haematoma particularly in the cerebellum, and supratentorial larger than 3 cm, despite
the fact that trials have failed to show any benefit of this practice. If the haemorrhage is due to
rupture of an aneurysm or AVM early surgical or endovascular intervention are important to
avoid re-bleeding .
Despite improvements in care, sequelae of stroke remain a major problem. Fifty to seventy per
cent of those who survive an ischaemic stroke will recover functional independence 3 months
after onset, but 20% will require institutional care. Stroke is the third leading cause of
disability and death in Europe after depression and IHD. Worldwide, stroke is the fifth
leading cause of disability and death.

6.6-4

6.6: Acute Stroke

The economic impact of stroke care goes beyond the costs of sophisticated acute care, costly
secondary prevention (carotid endarterectomy) and its prolonged high dependent institutional
chronic care as well as costs of rehabilitation. Neither mortality rate nor hospital discharges
accurately reflect the level of disability, which is mainly borne by patients and their families.
There is little progress being made in research and development of drugs for treating acute
stroke, particularly in the field of neuroprotection. Surprisingly low levels of resources have
been devoted to research and development of drugs for treating stroke during the last 30 years
(no more than 10% that invested in IHD or cancer).
Major improvements are needed in the chain of care for identification of stroke by relatives
(education); early treatment (possibly with aspirin); the prompt referral to an accident and
emergency facility (mobile units); accurate diagnosis and fast appropriate treatment (protocols
and specialized units); improving access to expanded and more efficacious therapeutic
options; and prompt referral to rehabilitation services.
As time is brain, more efficacious treatments provided early in the chain of care are needed
to minimise disability and avoid future suffering as well as reducing the economic costs in
societies with higher ageing populations.

6.6.1 Introduction
Definition and classification
Stroke, is defined as abrupt onset of a focal neurological deficit lasting more than 24 hours. It
is also called cerebrovascular accident (CVA) or apoplexy. 1 An acute stroke refers to the first
24-hour- period of a stroke. Focal neurological deficit lasting less than 24 hours (usually 520
minutes) known as transient ischaemic attack (TIA) is relevant but beyond the scope of this
discussion paper.
Stroke is classified on the basis of its aetiology as either ischaemic (80%) or haemorrhagic
(20%). Ischaemic stroke is produced by occlusion of a cerebral artery [thrombotic or
atherosclerotic (50%), embolic (25%) and microartery occlusion, lacunar stroke, (25%)].
Haemorrhagic stroke is caused mainly by spontaneous rupture of blood vessels or aneurysms
or secondary to trauma.2 The International Classification of Diseases versions 9 and 10 has
codified the different types as 430-438 and 160-169, respectively.

6.6-5

6.6: Acute Stroke

Natural history
Ischaemic stroke
Neurological symptoms and signs of an ischaemic stroke usually appear suddenly, but less
frequently, they occur in a progressive manner (stroke-in-progress). The typical presentation is
the sudden onset of hemiparesis in an older person. Symptoms and signs vary depending on
the location of the occlusion and the extent of the collateral flow.Atherosclerotic ischaemic
stroke is commoner in the elderly, and occurs without warning in more than 80% of cases. A
TIA a few months before the stroke is considered an important warning sign. 1 The
pathophysiology is similar to that of ischaemic heart disease; an atherosclerotic plaque in a
cerebral artery ulcerates triggering the aggregation of platelets and coagulation of fibrin to
produce the thrombus that occludes the artery. Fewer than 20% of cases do not evolve to
ulceration, but progresses to cause gradual obstruction of flow and may manifest as TIAs. In
hypertension-induced arteriosclerosis, small penetrating arteries of the deep white matter of
the brain are affected producing small infarctions known as lacunar infarcts. In around 40%
of elderly stroke patients no clear origin of the infarction can be found. .3;4
Embolic ischaemic stroke is more frequent in patients with atrial fibrillation (80%),
myocardial infarction, prosthetic valves, rheumatic heart disease and larger artery atheroma
(artery-artery embolus). Most emboli are of atherosclerotic origin, and may partially or
temporally obstruct cerebral arteries causing TIAs.5 Embolisms tend to be multifocal and may
produce small haemorrhages around the obstruction.
The occlusion of a cerebral artery causes a decreased blood flow and ischaemia. If it lasts only
few seconds or a minute, recovery is immediate and complete. Depending on the severity of
the ischemia, infarction (cellular death) will occur within minutes, causing irreversible damage
even after blood flow is restored. This is called the core of the infarct. Surrounding the core
is tissue that is affected functionally due to diminished circulation but may recover if blood
flow is restored.6-18 This is called the ischaemic penumbra of a stroke. Most people will have
an ischaemic penumbra amenable to treatment for 3 hours, but many patients may have it up
to 12 hours. This is known as the therapeutic window available for thrombolysis. Thus
proper identification of treatable patients is crucial for the efficacy of the interventions.
Due to changes in the vessels and parenchyma caused by ischaemia, the flow may not be
restored even after the original cause of the obstruction has been removed (no-reflow
phenomenon). Oedema is present in all necrotic tissue. In large areas of necrosis, massive
oedema compresses adjacent tissue, increasing intracranial pressure and may cause herniation
of the brain, leading to death within a few days in 80% of cases. 19-23 Surgical decompression has
been suggested for these cases. The extent of functional disability will depend on the extent
and the localization of ischaemia and complications experienced by the patient. 5

6.6-6

6.6: Acute Stroke

Seizures at the time of stroke occur in 35% of infarctions, more often after embolism than
thrombosis. The same proportion of patients will develop epilepsy from 6 to 18 months after a
stroke. Idiopathic epilepsy in the elderly, therefore, may be the result of silent cortical
infarction.1

Haemorrhagic stroke
There are two types; one resulting from intracerebral haemorrhage secondary to hypertension
or cerebral amyloid angiopathy, degenerative arterial disease and the other secondary to
subarachnoid haemorrhages caused by rupture of an aneurysm. In the United States, 810
million people (3% prevalence) might have one aneurysm and bleeding occurs in only 30 000
people per year. Other causes are uncommon, and sometimes, no source for the haemorrhage
can be found. The main risk factors are advanced age, heavy alcohol consumption and
hypertension. Cocaine abuse is an important cause of cerebral haemorrhage in young people. 1
Most intracerebral haemorrhagic strokes develop over 3090 min. Symptoms will depend on
the location and extent of the haemorrhage. Focal neurological symptoms, vomiting and
drowsiness are common. Headache may be present, but stiff neck and seizures are uncommon.
Large haemorrhages may cause stupor or coma. Most sub-arachnoid haemorrhages appear
suddenly with intense headache, vomiting and neurological deficit and altered consciousness
may occur in about 50% of patients. Occasionally, prodromal neurological symptoms, such as
paralysis of a limb, difficulty in speaking, visual impairment or sudden unexplained headache,
appear before a haemorrhage from an enlarging aneurysm causing pressure on the
surrounding tissue or as a result of a leak of blood into the subarachnoid space (warning
leaks).
Cerebral vasospasm is an early complication and re-bleeding or hydrocephalus may be
complications of SAH in 30% of cases during the first month, resulting in an extra 60%
mortality. Of those who survive, more than half will have significant disabilities. The annual
risk of recurrence of bleeding of an aneurysm is 3%. Thus, early surgical or intravascular
treatment of aneurysm in these patients improves their long term outcome. 1 The effectiveness
of evacuation of a supratentorial haematoma due to other causes has not been evaluated. 24
However, surgical removal of a large cerebellar haematoma is the current practice.

Investigation of a stroke
Outcome of investigations are crucial for effective management of acute stroke. Computerised
tomography (CT) is widely available, fast and probably the most useful imaging method in
identifying/differentiating cerebral haemorrhage from infarction. However, CT does not show
any abnormality within the first hour of an ischaemic stroke. Magnetic resonance imaging
(MRI), on the other hand, may be more useful in identify an ischaemic stroke but it is more
time consuming, not widely available in developing countries and special methods such as
diffusion weighted imaging is available only in specialist centres in developed countries. MR
or CT angiography demonstrates the cerebral vasculature and may add further information
such as aneurisms, segmental narrowing or complete blockage of blood vessels. Doppler
ultrasonography of carotid and vertebral vessels in the neck add further information and is
6.6-7

6.6: Acute Stroke

particularly useful in recommending patients for endarterectomy endovascular procedures or
intravascular thrombolysis treatment. Angiography performed by injecting a radio-opaque
dye directly into cerebral arteries via a catheter carries a significant risk of complications
according to age, the experience of the operator, etc (0.13-3% risk of complications).
None of these procedures is capable of accurately identifying ischaemic penumbra the most
important area of brain that is amenable to treatment in a patient with acute stroke. Newer
MRI diagnostic techniques such as diffusion-perfusion-weighted (DPW) imaging have been
tested for this purpose. 8-10;25-48 Diffusion-perfusion-weighted MRI and perfusion CT allows a
rought estimation of the penumbra and core areas in the acute phase of stroke. Although it has
been demonstrated that both MRI and CT can reliably detect intracranial haemorrhage in the
acute phase, MRI is not widely available, and access to emergent CT may be a problem in some
areas of Europe and the world. Further research into identification of neuronal integrity of the
penumbra during the so-called therapeutic window is essential for improving therapy for
stroke.

Assessment of acute stroke

The evaluation and treatment of patients with acute ischaemic stroke should be performed
without delay. The general and neurological history, together with brain imaging provide the
necessary information about the aetiology and potential contraindications to treatment with
thrombolytic agents. Brain imaging is currently mandatory to guide acute interventions. The
intervention protocols for haemorrhagic stroke are different from ischaemic stroke, and fatal
complications may result from misdiagnosis. Other clinical and para-clinical tests required are
not discussed here.
The National Institutes of Health Stroke Scale (NIHSS) has come into widespread use in the
United States for assessment of the severity of stroke and as an indicator of its prognosis. The
initial NIHSS score provides important prognostic information. Approximately 6070% of
patients with an acute ischaemic stroke with a baseline NIHSS score <10 will have a favourable
outcome after 1 year as compared with only 416% of those with a score >20.5

6.6.2 Burden of stroke

Graph 6.6.1: EU Stroke deaths

Epidemiology

(2002, by age and sex)

Source: WHO, Evidence, Information and Policy, 2003
200'000
180'000
160'000
140'000

Deaths

Stroke is the second leading cause

of death at the global level and in
the European region.49 Ten per cent
of the 55 million deaths that occur
every year worldwide are due to
stroke. Two-thirds of them occur
among people living in developing
countries.50 Almost a million cases
and two hundred thousand deaths
due to stroke occur in the EU alone
every year.49;51 Together with

EU25-M

120'000

EU25-F

100'000

EU15-M
EU15-F

80'000

EU10-M

60'000

EU10-F

40'000
20'000
0
0-4

5-14

15-29

30-44

45-59

Age groups

6.6-8

60-69

70-79

80+

6.6: Acute Stroke

cardiovascular diseases (CVD), these cases account for more than a third of all deaths in the
EU (Table 6.6.2).
There is a substantial difference in mortality between males and females: it is higher in males
under the age of 60 (1:1.7) and in females after the age of 70 (see graph 6.6.1). Overall stroke
mortality has been declining worldwide despite the increased percentage of people aged over
65 years (75% of stroke victims are above 65 years old). 52 This is mainly due to decreased
exposure to risk factors, mainly hypertension and smoking, and to improved access to better
healthcare.53 In Europe, stroke mortality is also declining although there are regional
differences (Fig. 6.6.3).
Table 6.6.2: Leading cause of deaths worldwide and in Europe (2002, percentage of total
deaths)
Global

EU25

EU15

EU10

IHD (12.57%)

IHD (18.11%)

IHD (16.79%)

IHD (24.45%)

Stroke (9.63%)

Stroke (10.90%)

Other CVD (10.78%)

Stroke (13.19%)

LRI (6.60%)

Other CVD (10.78%)

Stroke (10.42%)

Other CVD (10.77%)

HIV/AIDS (4.95%)

Trachea,
bronchus,
cancers (5.38%)

COPD (4.81%)

LRI (4.01%)

lung Trachea, bronchus, lung cancersTrachea,

bronchus,
(5.31%)
cancers (5.73%)
LRI (4.46%)

lung

Other cancer (3.96%)

IHD: Ischemic Heart Diseases; LRI: Low Respiratory Infections; CVD: Cardiovascular Diseases; COPD: Chronic Obstructive Pulmonary
Diseases; EU25: European Union with 25 countries; EU15: European Union with 15 countries; EU10: European Unions new accession
countries. Source: WHO, Evidence, Information and Policy, 2003.

Despite improvement in care, sequelae of stroke remains one of the major problems. Eight to
twelve per cent of ischaemic strokes and 3738% of haemorrhagic strokes result in death
within 30 days.54;55 Fifty to seventy per cent of patients who survive an ischaemic stroke will
recover functional independence 3 months after onset, but 20% will require institutional care.
Among patients above the age of 65 years, the severity of the attack and permanent disability
are greater. It has been reported that six months after the attack, 50% of stroke patients had
some hemiparesis, 30% were unable to walk without assistance, 26% were dependent on
others for help with activities of daily living, 19% had aphasia, 35% had depressive symptoms
and 26% were being cared for in a nursing home. 56 Stroke in childhood showed a moderate or
severe deficit in 42% of cases. 57 The burden of stroke can be reflected in a measurement such as
disability-adjusted life years (DALYs) or Quality-adjusted Life Years (QALY). Table 6.6.4 the
disability component of diseases in terms of DALYs, ranking stroke third in Europe after
depression and IHD.

6.6-9

6.6: Acute Stroke

Graph 6.6.3: Standardized death rates cerebrovascular diseases, all ages per 100.000
Source: Health for All Database, WHO-EURO 2004
090302 +SDR, cerebrovascular
diseases, all ages per 100000

150

140

130

120

110
EU-25 average
EU-15 (MSs prior 1.5.2004) average
EU-10 (MSs after 1.5.2004) average

100

90

80

70

60

50
1970

1980

1990

2000

2010

Table 6.6.4 : Burden of diseases and injury worldwide and in Europe (2002, percentage of
total DALYs)
Global

EU25

EU15

EU10

LRI (5.83%)

Depression (7.76%)

Depression (7.87%)

IHD (9.98%)

HIV/AIDS (5.77%)

IHD (7.40%)

IHD (6.76%)

Depression (7.31%)

Depression (4.51%)

Stroke** (5.27%)

Stroke** (5.03%)

Stroke** (6.23%)

Diarrhoea (4.10%)

Alcohol use (4.21%)

Alcohol use (4.36%)

Other CVD (3.94%)

IHD (3.91%)

Other CVD (3.85%)

Alzheimer* (3.91%)

Alcohol use (3.57%)

Stroke (3.29%)

Alzheimer* (3.48%)

Other CVD (3.83%)

TBLC (3.43%)

OUI (3.26%)

HL (3.43%)

HL (3.61%)

OUI (3.40%)

LBW (3.11%)

TBLC (3.28%)

COPD (3.44%)

ODD (3.37%)

Malaria (3.00%)

COPD (3.05%)

TBLC (3.25%)

Osteoarthritis (2.76%)

OID (2.68%)

ODD (2.79%)

ODD (2.64%)

HL (2.69%)

* Alzheimer and other dementias; ** cerebrovascular diseases; LRI, lower respiratory infections; IHD, ischaemic heart disease; OUI, other
unintentional injuries; LBW, low birth weight; OID, other infectious diseases; HL, hearing loss, adult onset; TBLC, trachea, bronchus, lung cancers;
COPD, chronic obstructive pulmonary disease; ODD, other digestive diseases. EU25: European Union with 25 countries; EU15: European Union

with 15 countries; EU10: European Unions new accession countries. Source: WHO, Evidence, Information and Policy, 2003

6.6-10

6.6: Acute Stroke

Due
to
ageing
populations,
especially
in
those
countries
currently
undergoing
rapid
economic growth, projections to
2020 suggest that stroke will remain
the second leading cause of death. In
addition, stroke will be among the
five most important causes of
disability in both developing and
developed countries50 (Table 6.6.5).
There are no projections available
for the EU).

Economic impact

Table 6.6.5: Burden of disease and injury (DALY, global)

2000

2020

1. Acute lower respiratory

1. Ischaemic heart disease

infections

2. Unipolar major depression

2. Human immunodeficiency
virus/acquired immunodeficiency
syndrome

3. Road traffic accidents

3. Perinatal conditions

5. Chronic obstructive

4. Diarrhoeal diseases

pulmonary disease

5. Unipolar major depression

6. Lower respiratory infections

4. Cerebrovascular disease

7. Tuberculosis
6. Ischaemic heart disease
The largest components of acute care
Fig.
6.6.6:
Hospital
discharges,
Cerebrovascular
disease,
Source: Lancet 1997;349:1498-1504 & WHO, Evidence, Information
and Policy, 2000.
costs in the United States are room
8.
War
7. Cerebrovascular disease
990902
per +Hospital
100.000; discharges,
Source: WHO Health for All Database.
charges (50%), medical management
cerebrovascular diseases per 100000
400
(21%) and diagnostic costs (19%).58
9. Diarrhoeal diseases
8. Malaria
The economic impact of stroke goes
10. Human immunodeficiency
9. Road traffic accidents
beyond the cost of acute care to
350
virus
include sophisticated and costly
10. Chronic obstructive pulmonary
secondary prevention such as
EU-25 average
carotid endarterectomy and its
disease 300
EU-15 (MSs prior 1.5.2004) average
EU-10 (MSs after 1.5.2004) average
prolonged, highly dependent chronic care.
The estimated mean lifetime cost per
250
ischaemic stroke patient in the United States
is US$ 140,048 in 1999. This includes
inpatient care, rehabilitation and follow-up
200
care necessary for lasting disabilities. 59 In
1980
1985
1990
1995
2000
2005
2010
2004 the estimated total direct and indirect
cost of stroke in the United States is US$ 53.6 billion. 52

In the European Union, hospital discharges for cerebrovascular diseases almost doubled
during the last 15 years of the twentieth century (Fig. 6.6.6) In the United States, the same
pattern has been reported for the same period.Average length of hospital stay fell from 11.1 to
6.2 days and the total number of persondays in hospital decreased by 22%.60 Specialized
stroke care has been shown to improve health and economic outcomes. 61;62 Similar trends are
observed for mortality and case fatality rate could be lowered by improved stroke services.
Neither mortality rate nor discharges from hospital accurately reflect the level of disability,
which is mainly borne by patients and their families. Stroke has been associated with greater
use of informal care (family and friends).63 Health care costs are increasing despite the
decrease in stroke incidence and mortality, and will continue to increase as our societies age.

6.6-11

6.6: Acute Stroke

Priorities, therefore, should be placed on primary prevention of stroke, effective treatment of
acute stroke to minimise unfavourable sequelae and extend stroke management outside the
hospital to improve accessibility and reduce hospital costs.

6.6.3 Control strategy

Stroke prevention
Risk factors
Stroke prevention is still the best available intervention. High blood pressure is one of the
major primary and secondary risk factors for stroke, for which major professional associations
worldwide have published detailed clinical management guidelines that might be highly costeffective in high-risk populations.64-66 Reducing other risk factors, such as smoking, diabetes
(obesity and lack of exercise), and heavy alcohol consumption have been shown to provide
health benefits including reduction of stroke and might be highly cost-effective. 67

Acute ischaemic stroke

The successful management of acute stroke is based on two strategies:
a) Vascular recanalization
Because most strokes are due to thromboembolic occlusion of an intracranial artery, restoration
or improvement of perfusion to the ischaemic area is the key therapeutic strategy. The concept
of an ischaemic penumbra, a potentially recoverable brain tissue, allows early intervention to
improve the neurological symptoms, and decrease the functional disability after the attack.
There are many strategies suggested for treatment of acute stroke, but only oral aspirin and
intravenous rt-PA have been clearly proven to be effective and their use has now been
approved by regulatory agencies.24
Anti-platelet Agents: The use of antiplatelet agents is highly controversial. Aspirin, 150300
mg once by mouth, has been found one percent more effective than placebo in reducing death
and disabilities at 6 months after onset in patients with ischaemic stroke. There has been no
increased risk of death among those subsequently found to have a haemorrhagic stroke. 68;69
Some authors recommend not delaying the administration of aspirin even if imaging diagnosis
is not available during the first 48 hours 24 or haemorrhagic stroke has been excluded by CT or
MRI.2 Side-effects such as abdominal pain, peptic ulcerations and allergy to Aspirin may limit
its wider use.70 Clopidogrel is an alterative when aspirin cannot be used. Anticoagulants, such
as Warfarin, have not been shown to produce better outcomes than aspirin alone .71 No other
antiplatelet agent has yet been reported effective.24;72
Thrombolysis: The intravenous administration of rt-PA (0.9 mg/kg; maximum dose 90 mg)
within 3 hours of onset of ischaemic stroke has been approved by the US Food and Drug
Administration (FDA) and EU regulators for the treatment of acute ischaemic stroke. 45
Treatment with rt-PA is associated with potentially fatal intracranial haemorrhage in 6.3% of
cases (versus 0.6% of cases treated with placebo). The safety and efficacy of rt-PA for the
treatment of children has not been established. Common side-effects include bleeding from
6.6-12

6.6: Acute Stroke

cuts, gums, wounds, injection sites, fever and low blood pressure. 73 Because of potential fatal
complications thrombolytic treatment should be carried out according to a strict predetermined protocol.
To date, no other thrombolytic agent has been established as a safe and effective alternative to
intravenous rt-PA. Currently available data do not support the clinical use of either
streptokinase or ancrod.24;74 Promising results have been reported in trials of prourokinase, but
the risk of haemorrhagic stroke is high.75-77
As the ischaemic process progresses very fast, the time at which treatment starts has been
shown to be critical if there are to be significant benefits. Treatment within the first 3 hours has
been defined as the therapeutic window for acute stroke, but evidence suggests that earlier
treatment brings a better outcome.
As Intracranial haemorrhage is difficult to treat it must be avoided at all costs. In the National
Institute of Neurologic Diseases Study (NINDS) of rt-PA showed the NIHSS score to be useful
in identifying patients with higher haemorrhagic risk. Patients with a score of 20 or more on
the NIHSS had a 17% chance of intracranial haemorrhage, whereas the risk of bleeding was
only 3% among those with a score <10.5
The size of the infarct, based on CT, is also a predictor of haemorrhage and poor outcomes, but
no study has yet determined whether treatment of severe cases with rt-PA might have higher
risks than benefits. As a result, it has been suggested that the performance of these tests should
not delay treatment with intravenous rt-PA.5 Other investigations, including imaging of
cerebral vessels, carotid Doppler studies, cardiac echo can be delayed until after the
thrombolytic treatment.
b) Supportive care
When cerebral infarction occurs, the immediate goal is to optimize cerebral perfusion of the
ischaemic area, monitor potential stroke-related complications (cerebral oedema, seizures,
haemorrhagic transformation, cardiovascular and pulmonary problems, fever and malignant
hypertension) and to prevent the common complications of bedridden patients, such as
malnutrition, infections, pressure sores, aspiration pneumonia, deep venous thrombosis and
pulmonary embolism. Early mobilisation is very useful in preventing these complications.
The provision of airway support and ventilatory assistance for patients with acute stroke who
have depressed levels of consciousness or airway obstruction may be necessary. A further
recommendation is to provide supplementary oxygen only to hypoxic patients. Fever is
associated with poor outcomes and should be treated with antipyretics with no antiplatelet
effect. There is general agreement to recommend control of hypoglycaemia or hyperglycaemia
following stroke. A reasonable goal would be to lower markedly elevated glucose levels to
<300 mg/dL (<16.63 mmol/L).1
As cardiovascular diseases (mainly myocardial infarction and arrhythmias) are risk factors and
complications of an acute stroke, they should be carefully evaluated and treated using
established protocols in stroke patients. Use of anticoagulants during the first 14 days should
be avoided. Hypertension may be a serious complication is some cases, but there is no
6.6-13

6.6: Acute Stroke

evidence to support aggressive treatment unless systolic blood pressure is >220 mmHg or the
diastolic blood pressure is >120 mmHg.78
Once the patient has been stabilized patient and family education, screening and treatment of
depression, and physical and functional rehabilitation should start as soon as possible. Finally,
the patient should have further evaluation to determine the cause of the stroke, and medical or
surgical therapies should be administered to prevent recurrent ischaemic events.
Acute haemorrhagic stroke
In most patients with a haemorrhagic stroke, bleeding has already stopped by the time they
arrive at the hospital. Except in patients with a bleeding disorder, nothing can be done about
the haemorrhage itself. Nevertheless, Mayer et al recently reported that early administration of
clotting factors may be beneficial for all patients. 79 The assessment should be done in
consultation with a neurosurgeon. The size and location of the haematoma determine the
prognosis. current treatment focuses on evacuation of the haematoma particularly in the
cerebellum, and supratentorial larger than 3 cm, despite the fact that trials have failed to show
any benefit of this practice.24 If the cause is rupture of an aneurysm, pain management and
early surgical or endovascular repair of the aneurysm are important to avoid re-rupture (60%
risk with poor prognosis).
Antifibrinolytic agents may be used in patients in whom treatment is delayed. They are
associated with a reduced incidence of aneurysmal re-rupture but are also associated with an
increased incidence of delayed cerebral infarction. Because of the increased risk of ischaemic
complications, antifibrinolytics are not routinely given to patients who are at risk for
developing vasospasm.

6.6.4 Major problem and challenges of stroke management: why does

the disease burden persist?
The process of care begins with calling an ambulance or personally on arriving in an accident
and emergency facility. In one study in an urban area in the United States, only 17% of patients
were admitted to hospital within the 3 hour therapeutic window 80 and in an international trial,
only 4% of patients were admitted within 3 hours of symptoms onset. 69 Inadequate public
education on stroke and the patients perception that his or her symptoms are not severe
enough are the major causes of delays in attending a health service in developed countries.
Only 5% of patients in developed countries have access to tr-PA within the therapeutic
window and mobile stroke units are still at the experimental stage. 69 Lack of access to general
health services might be an important factor in delayed treatment in developing countries.
Once the patient is in contact with the health system a number of major barriers to treatment
within the therapeutic window have been identified. Lack of specific protocols and training ,
delay in obtaining a diagnostic imaging test, delay in referring the patient to a specialized
stroke unit and the low efficacy of available treatments (aspirin 1% and rt-PA 10% superior
than placebo) are some of these factors in developed and developing countries. Lack of access
to rt-PA might be an important factor in developing countries.

6.6-14

6.6: Acute Stroke

Most patients with stroke are over the age of 65 years, and often present comorbidities that
add complexity to the management of the condition. Stroke is highly unstable during the acute
phase and requires close monitoring and prompt attention to complications. Access to highly
skilled professionals and the availability of costly resources have been shown to improve
overall outcomes.72;81 The integration of rehabilitation services with acute hospital care has also
been shown to be effective in improving health outcomes.81
Thus the major challenge of stroke are facing the world population at large are early diagnosis
and referral of patients to specialized units; the inadequate number of highly specialized
professionals, unavailability of complex and costly care, limited therapeutic options, and the
low efficacy of the available interventions.
An additional yet extremely important challenge is the insufficient funding for research and
development of new products and protocols for stroke management. Funding for stroke
research falls far behind the resources devoted to other major conditions, such as ischaemic
heart diseases and cancer.82;83

6.6.5 Past and current research into pharmaceutical interventions for

managing stroke
Progress in stroke research has been modest but significant. Developments in vascular and
functional brain imaging have improved the detection of patients at increased risk and in the
future it might be possible to identify those who are likely to benefit from a specific
intervention. Developments in cell biology and new imaging techniques have improved our
understanding of cerebral ischaemia.
The National Institutes of Health reported on 101 ongoing clinical studies on stroke, of which
35% evaluate the natural history of stroke, including risk factors, normal and pathological
physiology, and descriptive epidemiology; 14% on prevention; 1% on diagnosis; 26% on
rehabilitation; 11% on acute stroke treatment (1% thrombolytic coadjutants, 4% thrombolytic
agents, 1% antiplatelets, 3% neuroprotectors and 2% cellular modulators); and 13% on
alternative treatments and treatments for stroke-related comorbidities. 84
The Stroke Trials Directory details ongoing and already completed clinical trials throughout
the world85 (Tables 6.6.7 and 6.6.8). From these, only three new products have shown
promising results; Pro-urokinase75 and Tenecteplase, intra-arterial thrombolysis agents, and
Ancrod,86 a defibrinogenating agent. All other trials have either failed to show benefits or have
higher risks than benefits, while some are still in the early stages, so no conclusions could yet
be drawn.
All neuroprotective agents that have shown positive results in animal models have failed when
tested in humans (Table6.6.8). Many possible explanations for this failure have been proposed.
For example, animal models were not designed to represent the realities of human health care
(eg. difficulties with early treatment), inadequate translational techniques, underpowered

6.6-15

6.6: Acute Stroke

phase III trials, inclusion of patients unlikely to respond to the trial drugs, and inappropriate
measurement end-points.72

6.6-16

6.6: Acute Stroke

Table 6.6.7: Drugs to improve blood flow

Anti-thrombotic:
Heparin (NB)
Low-molecular-weight heparins:
Dalteparin (PO/OT)
Enoxaparin (Un)
Nadroparin (NB/PH)
Tinzaparin (AT/OT)
Danaparoid (NB)
Anti-platelet
Aspirin (B)
Abciximab (AT/OT)
Tirofiban
Clopidogrel
Fibrinogen-depleting
Ancrod (NB/OT)
Defibrase (Un)
Improve capillary flow
Pentoxifylline (Un)
Thrombolytics
Pro-urokinase (B/OT)
Streptokinase (H)
Tenecteplase (B/OT)
Tissue plasminogen activator (B/FDA)
Urokinase (Un)
Desmoteplase

Symbols:
AT/OT: Acute treatment/ongoing trials
B/FDA: Beneficial/FDA approved for stroke
B/OT: Beneficial/ongoing trials
B: Beneficial
H: Harmful
NB/OT: No benefits/ongoing trials
NB/PH: No benefits/potential harm
NB: No benefits
OT: Ongoing trials
PO/OT: Prevention only/ongoing trials
S/OT: Safe/ongoing trials
Un: Unknown

6.6-17

Table 6.6.8: Drugs to protect brain tissue

Calcium-channel blockers
Nimodipine (B/FDA for haemorrhagic stroke
and NB/OT for ischaemic)
Flunarizine (NB)
Calcium chelator
DP-b99 (S/OT)
Free radical (antioxidants & nitrone traps)
Ebselen (NB/OT)
Tirilazad (NB/PH)
NXY-059
GABA agonists
Clomethiazole (NB)
Glutamate antagonists (NB or OT)
AMPA antagonists: GYKI 52466; NBQX; YM90K;
YM872; ZK-200775 (MPQX)
Kainate antagonist
SYM 2081
NMDA antagonists
Competitive NMDA antagonists
CGS 19755 (Selfotel)
NMDA channel blockers: Aptiganel (Cerestat);
CP-101,606 ; Dextrorphan ; Dextromethorphan ;
Magnesium ; Memantine ; MK-801 ; NPS 1506 ;
Remacemide
Glycine site antagonists: ACEA 1021 ; GV150526
Polyamine site antagonists: Eliprodil ; Ifenprodil
Growth factors (NB/PH)
Fibroblast growth factor (bFGF)
Leukocyte adhesion inhibitor
Anti-ICAM antibody (H)
Hu23F2G (NB)
Nitric oxide inhibitor
Lubeluzole (NB)
Opioid antagonists
Naloxone
Nalmefene (NB/PH/OT)
Phosphatidylcholine precursor
Citicoline (CDP-choline: NB)
Serotonin agonist
Bay x 3072 (OT)
Sodium channel blockers
Fosphenytoin (NB)
Lubeluzole (NB)
619C89 (OT)
Potassium channel opener
BMS-204352 (NB)
Mechanism unknown or uncertain
Piracetam (NB)
Lubeluzole ((NB)

6.6: Acute Stroke

Investment in research and development on stroke is minute compared to the funding
available for the other two major conditions, CHD and cancer, and this is totally out of
proportion to the burden caused by the illness. Rothwell found that funding for stroke
research in the United Kingdom, was only 5% of the available funds of the biggest donor in
this area, the British Heart Foundation, and only 2% of the amount devoted to research on
cancer by the two largest cancer foundations, the Imperial Cancer Research Fund and the
Cancer Research Campaign. In the USA, the American Heart Association, devotes only 4.6% of
its funding to stroke. The same pattern is seen in disease-specific governmental organizations,
such as that of the EU and the National Institute of Neurological Disorders and Stroke (US$
200M of an overall annual budget of US$ 900 Millions). 82 Pendlebury et al has shown that this
pattern is fairly homogeneous among nine European countries studied.83
The UK National Health Service (NHS) spends 2.3 billion on stroke care annually, which
represents 6% of its overall budget. Stroke in comparison to CHD utilizes almost twice as
much health care resources and places a much greater financial burden on disabled patients
and their families.82 Yet resources dedicated to stroke research and development are a mere
one tenth of those devoted to CHD. This is just 0.2% of the overall budget for stroke care of the
UK National health services.
There is an evident mismatch between the funds allocated to research and development and
the burden of stroke, whether measured in terms of mortality or disability. Lack of funding
undermines the capacity to do good research to an extent that stroke scientists are no longer
able to apply for the further required funding. For many years, this has been a vicious cycle
that has delayed progress in stroke research. Rational decision-making processes, taking into
consideration the burden of diseases, are used by governments to decide the amount of public
expenditure to be directed towards pharmaceutical and medical technologies in developed
countries. The same tools or adaptations of these tools should be used for guiding investment
decisions on pharmaceutical research and development.

6.6.6 What are the opportunities for research into new pharmaceutical
interventions that might fill the current gap and make a substantial
difference?
Opportunities for research can be divided into four categories:
a) reducing treatment delays;
b) identifying those patients who can benefit the most from a product;
c) prolonging the treatment window; and
d) therapies that work outside the treatment window.

Strategies for reducing treatment delays

The use of rt-PA in mobile stroke units at the first contact with the patient and prompt referral
to specialized centres, has been highly effective in improving health outcomes. As rt-PA is
6.6-18

6.6: Acute Stroke

contraindicated in patients with haemorrhagic stroke or those likely to have it as consequence
of the treatment, research is required to develop and test diagnostic protocols to be used by the
paramedics in these units. In order to avoid duplication of ambulance systems, the use of rt-PA
by paramedics should be considered in normal ambulances rather than in mobile stroke units.
The current major drawback is inaccessibility to CT scanning.
Another area of research is the development of safer drugs that could be used earlier in
sequence with stronger intervention later in hospital. Aspirin is shown to be effective in
improving health outcomes in acute stroke. It is safer for patients with haemorrhagic stroke
and is readily available. Further research is required to evaluate the cost-effectiveness of using
aspirin at the time of onset of symptoms at home, in the ambulance or on arrival at the
hospital in relation to its interaction with rt-PA at different dosages; and the additional risk for
patients with haemorrhagic stroke that may have been misdiagnosed as ischaemic stroke.

Identifying the patients who can benefit the most from a specific product
Drug efficacy may be lower and/or drugs may have a higher profile of side-effects for
erroneous reasons, e.g. trials may have included patients who no longer have an ischaemic
penumbra, or who have experienced different physiopathological mechanism, or who were
admitted using different concomitant treatment. Such patients should be identified and
included in trials designed specifically for them.
Diagnosis using perfusiondiffusion MRI and CT may delineate the existence and extent of the
ischaemic core, the extent and severity of perfusion impairments, occlusion of large vessels,
and the ischaemic penumbra. It has also shown promising results in predicting health
outcomes and identifying patients with treatable ischeamic penumbra beyond the standard 3hour therapeutic window. Several studies are currently evaluating some of these issues (the
DWI Evaluation for Understanding Stroke Evolution (DEFUSE), the Echo Planar Imaging
Thrombolytic Evaluation Trial (EPHITHET), the Desmoplase in Acute Stroke (DIAS) and the
Stroke Evaluation for Late Endovascular Cerebral Thrombolysis). Further research is needed to
evaluate feasibility of these techniques to be used clinically in resource-poor settings and also
to be able to match specific treatments to specific patients using more advanced techniques.

Prolonging the treatment window

Therapies with the so-called neuroprotectives that is aimed at slowing down the cascade of
events leading to cell death have been tested, but the results have been disappointing. These
unfavourable results might have been the product of many methodological errors. If
neuroprotectors are to be effective in slowing down cell death this may be very useful in
prolonging the therapeutic window, and therefore the management of acute stroke. Some
publications have suggested that it would be beneficial to begin the use of neuroprotector
earlier in the chain of care, before treatment with fibrinolytic agents. 72 More funding is
urgently needed in this specific area of research.

6.6-19

6.6: Acute Stroke

Treatments for late intervention
Many therapies that are not indicated in the early stages of care because of serious
complications such as cerebral haemorrhage, but they may be useful at later stages when
haemorrhages are less likely to occur. Some other therapies target mechanisms that appear
several hours after the onset of the symptoms. Exploitation of such therapies will significantly
increase the number of patients that could be treated leading to major improvements in
healthcare provision.

6.6.7 Conclusions
Ischaemic stroke produces irreversible cellular death within a few minutes. Surrounding the
ischaemic core is the tissue that is affected by ischaemia, but still functional and recoverable.
Any therapeutic measures should be directed in stopping the progression of the ischaemia and
achieving functional recovery of tissue as soon as possible. The nature of the disease is such
that time is the major constraint in the management of acute ischaemic stroke. Hence the
phrase time is brain, has been coined by workers in this field.
The management of patients with acute ischaemic stroke requires multiple interventions, an
accurate initial diagnosis, close monitoring of potential complications and skilled highly
trained professionals. The evidence suggests that mortality can be reduced further and
neurological disability can be avoided or improved with the appropriate treatment of acute
stroke.
Major improvements in stroke care have been made in recent years. Rapid referral of patients
to a specialized stroke unit, the administration of rt-PA within the 3 hour therapeutic window
and the provision of intensive general care, have made a real difference.
There is a still long way to go. Major improvements are needed in the chain of care, in the
identification of an attack by relatives (education), early treatment (aspirin?), the prompt
referral to an accident and emergency facility (mobile units), accurate diagnosis and fast and
appropriate treatment (protocols and specialized units), improving access to efficacious
therapeutic options, and prompt referral to rehabilitation services.
The results of trials of therapies currently in the pipeline have been disappointing, especially
in the field of neuroprotectors. This is not different to the situation with many other
conditions in the early stages of research. The difference is that due to insufficient funding
stroke research had suffered and had not made major advancement in 30 years!
The decrease in mortality is due to the provision of complex and costly general care and not as
a result of salvaging the ischaemic brain by specific stroke therapy. Most patients sadly have
significant disability when they are discharged from the hospital where the society is expected
to support.
More efficacious treatments provided earlier in the chain of care are needed to avoid future
suffering and the economic cost of increasing disability in rapidly ageing societies.

6.6-20

6.6: Acute Stroke

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