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STROKE
What is stroke?
A stroke is sudden damage to blood vessels in the brain that
causes symptoms lasting for more than 24 hours (most usually
paralysis affecting one side of the body and/or speech difficulties).
If such an event clears up spontaneously within less than 24 hours,
it is termed a transient ischaemic attack (TIA). The majority of
strokes in Western countries (about 85 per cent) are ischaemic
strokes, which result from arterial blockage by a blood clot
(Figure 1) or detached plaque from elsewhere in the circulation
(see Atherosclerosis). Most of the rest are a result of brain
haemorrhage (bleeding from a ruptured blood vessel into the
brain), and in this type of stroke there may be severe headache
and vomiting, as well as paralysis and speech difficulties.
Brain damage in stroke is caused by a reduction in the oxygen
supply to the brain and chemical changes resulting from it. The
brain consumes oxygen at a high rate, but has no oxygen reserve.
Hence, it is entirely dependent on a continuous blood supply
through the carotid and vertebral arteries.
There is a more insidious side to strokes. Many people experience
a series of mild ischaemic strokes over a period of years. These
may be unnoticed - silent ischaemia - or cause transient symptoms,
but over time the accumulated damage is responsible for about 25
per cent of cases of senile dementia.
Who does stroke affect and what does it cost?
More than 130,000 people a year suffer a stroke in England and
Wales and 60,000 die of cerebrovascular disease, making stroke
the third most common cause of death, after heart disease and
cancer. Between 15-20 per cent of people experiencing a stroke
die within a month. Of those that survive, some do not regain the
full use of their faculties. More than 300,000 people in the UK are
believed to live with moderate to severe disability as a result of
a stroke.
Although stroke can affect younger people, it is largely a disease of
older age (Figure 2) and 85 per cent of strokes are in the over-65s.
It is well recognised that there are risk factors for stroke apart from
age. The clearest is high blood pressure (see Hypertension), while
smoking, heavy drinking and diabetes also play a part.
Strokes are estimated to have cost the NHS over £2.8 billion in
direct costs in 2004, being responsible for over 2.6 million beddays
of hospital care in 2003/04. In addition, informal care costs
have been estimated at £2.4 billion and indirect costs due to loss
of income and disability benefit payments at £1.8 billion, giving a
total cost to society of £7 billion year due to strokes.
Present treatments and shortcomings
Medical treatment for stroke has two different objectives:
- emergency treatment to limit damage in the hours and days
following an acute stroke
- prevention of a first or subsequent stroke (over a long period).
Emergency treatment is complicated by the fact that there are two
different causes of stroke (clots and haemorrhage), which may be
difficult to distinguish in the initial clinical examination. Brain
scanning by computed tomography or magnetic resonance imaging
is needed to distinguish between these, but is not always available.
A therapy suitable for a clot-induced stroke (for example,
clot-busting and 'blood thinning' medicines) would be potentially
harmful in a haemorrhagic stroke, as it might make the bleeding
worse and cause even greater brain damage. For this reason,
medicines (heparins and fibrinolytics such as streptokinase and
urokinase) that are available for use in heart attack, deep vein
thrombosis and post-operative prevention (see Ischaemic Heart
Disease and Thrombosis) are generally not indicated for use in
stroke in the UK. Only one, the 'clot-buster' enzyme alteplase
(Actilyse, Boehringer Ingelheim), is currently available for acute
management of stroke, and this may only be used where
haemorrhagic stroke has been ruled out by brain imaging.
Prevention of stroke includes both minimising risk factors, for
example by treating high blood pressure, and the long-term use of
medication that can prevent the development of ischaemic stroke.
Daily low-dose aspirin reduces platelet stickiness and decreases
the risk of recurrent stroke by about 15 per cent. Clopidogrel
(Plavix, sanofi-aventis and BMS) and dipyridamole (Persantin
Retard, Boehringer Ingelheim) are other anti-platelet agents also
available for this purpose. Anti-platelet medicines are not used in
those who have had a haemorrhagic stroke.
Some antihypertensives, such as ACE-inhibitors and angiotensin
receptor blockers, have been shown to prevent heart attacks and
stroke in those with established cardiovascular disease. Statins
have also been shown to reduce the risk of stroke, but have not
been explicitly indicated for this purpose. Atrial fibrillation (see
Cardiac Arrhythmia) carries a high risk of stroke, and many people
with this condition will be given anticoagulation treatment with
warfarin to minimise this risk.
What's in the development pipeline?
Emergency treatment of ischaemic stroke seeks to restore
circulation to affected brain areas as far as possible, to limit
the extent of nerve cell death, and thus preserve brain function.
Several companies have projects to develop alternative
clot-digesting agents. At Phase 3, these include ImaRx
Therapeutics's PROLYSE, ancrod (Viprinex, Neurobiological
Technologies), which is derived from Malaysian viper venom,
and desmoteplase (Paion/Lundbeck/Forest Labs), based on a
protein originally isolated from the saliva of vampire bats. At the
Phase 2 stage is V10153 (Vernalis), which is expected to both
dissolve an existing clot and prevent new clots from forming.
Brain cell stress in acute stroke results from oxygen and energy
deprivation. It is thought to lead to accumulation of the
neurotransmitter glutamate and a massive influx of sodium and
calcium ions into neuronal cells. This leads to activation of
calcium-dependent enzymes, the generation of damaging reactive
molecules such as free radicals, and the initiation of programmed
cell death (apoptosis). Many attempts have been made to stop this
toxic 'glutamate cascade' by treatment with neuroprotectants that
act on one or other step in the process. However, although this has
been achieved in animal models, human trials have so far largely
failed to show clinical benefit, perhaps partly because of inevitable
delays in starting treatment (more than three hours after the event),
by which time damage may be irreversible.
Despite earlier disappointments, several companies have potential
medicines to protect nerve cells in development. At Phase 2,
D Pharm has the calcium-binding compound DP-b99 and Paion is
working on enecadin, a blocker of sodium and calcium channels.
Taking a different approach are Daiichi-Sankyo, which has
piclozotan in Phase 2 trial, and Ono and Merck Sharp & Dohme,
who are investigating a compound (ONO-2506) that modulates the
activity of astrocytes - cells which surround and support nerve cells
in the brain. Ono is also conducting a Phase 1 study of
ONO-2231 for this indication.
Stroke prevention is also still a focus of development, particularly
in the context of atrial fibrillation. The most advanced projects
here are dabigatran etexilate (RENDIX, Boehringer Ingelheim),
idraparinux (sanofi-aventis) and a modified form of idraparinux
(SSR 126517, sanofi-aventis), which are all in Phase 3 trial. Bayer
has BAY 59-7939 (rivaroxaban) in Phase 2 trial and Solvay is
studying SB 424323 (odiparcil) at the same stage. GSK also has
GSK 813893 in a Phase 1 study and Trigen has TGN 167 at
this stage.
Further trials of anti-platelet medicines for stroke prevention
are also continuing. Boehringer Ingelheim is comparing the
combination of extended-release dipyramidole plus aspirin
(Asasantin Retard) with clopidogrel (Plavix, sanofi-aventis). The
study will also test whether addition of the angiotensin receptor
blocker telmisartan (Micardis) can further reduce stroke risk in
patients who have already had one stroke. In a different setting,
Eli Lilly is testing the ability of the anti-platelet agent prasugrel to
prevent strokes in people with acute coronary syndrome (heart
attack or unstable angina) undergoing angioplasty.
Lastly, there are new developments too in treating haemorrhagic
stroke. Novo Nordisk is running a Phase 3 trial of its NovoSeven,
which has shown evidence in earlier Phase 2 trials of an ability to
limit the extent of bleeding into the brain if administered within
three hours of stroke onset. Evidence of a reduction in post-stroke
disability in this setting would be a very welcome step forward.
FOR FURTHER INFORMATION CONTACT:
THE STROKE ASSOCIATION
Stroke House, 240 City Road
London, EC1V 2PR
Phone: 0845 303 3100 (Helpline)
Website: www.stroke.org.uk
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