Strokes occur when the blood supply to the brain is disrupted, leading to brain damage. They most often occur in people over 65 years old. Medicines to prevent strokes have reduced deaths over the past 30 years. Further research into brain cell death is underway. Preventing or successfully treating strokes could reduce the need for hospitalisation and intensive rehabilitation.
A stroke is defined as a vascular event in the brain that causes abnormal neurological function lasting for more than 24 hours. About 85 per cent of strokes in Western countries are ischaemic strokes, which result from arterial blockage by a blood clot or detached plaque from elsewhere in the circulation. Most of the rest are a result of brain haemorrhage, often caused by the rupture of an aneurysm.
Brain damage arises as a result of oxygen depletion: brain tissue 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. It is well recognised that there are risk factors for stroke apart from age. The clearest is high blood pressure, while smoking, heavy drinking and diabetes also play a part.
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 pre-senile and senile dementia.
In the European Union, around one million people a year suffer a first stroke and 600,000 die of cerebrovascular disease, making stroke the 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.
Some two million people in the EU are believed to live with disability as a result of stroke. Although stroke can affect younger people, it is largely a disease of older age and 85 per cent of strokes are in the over-65s. Indeed, 25 percent of men and 20 per cent of women can expect to suffer a stroke if they live to be 85 years old. Because of the increase in the elderly population, the total incidence of stroke is projected to increase considerably over the next two decades. It is predicted that stroke will account for six per cent of the total burden of illness in 2020.
Medical treatment for stroke has two different objectives:
(i) emergency treatment to limit damage in the hours following an acute stroke, and
(ii) 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 it may be difficult to distinguish rapidly in the clinic. A therapy suitable for a clot-induced stroke, e.g. clot-busting and blood thinning medicines, would be potentially harmful in a haemorrhagic stroke, as it might perpetuate bleeding and cause even greater brain damage. In patients suffering from stroke caused by a ruptured aneurysm, intervention by neurosurgery may apply.
Prevention of stroke includes both minimising risk factors, for example by treating hypertension, and the long-term use of medication that can prevent the causes of ischaemic stroke. Daily low-dose acetylsalicylic acid reduces platelet stickiness and decreases the risk of recurrent stroke by about 15 per cent. There are other anti-platelet medicines approved for the secondary prevention of stroke.
Anti-platelet medicines are not recommended in those who have had a haemorrhagic stroke. The cholesterol-lowering statins have also been shown to reduce the risk of stroke, clinical trials to prove this indication are ongoing, especially in elderly people with hypertension and hyperlipoproteinaemia. Recombinant human plasminogen activator is available for the treatment of clot-induced stroke.
Because of the link between hypertension, atherosclerosis and stroke, many pharmaceutical companies are involved indirectly in stroke prevention through their research programmes in these other areas, and are already contributing significantly to increased life expectancy. Companies are also studying stroke directly.
Research groups have shown that treatment with a combination of an angiotensin converting enzyme (ACE) inhibitor and a diuretic reduces stroke occurrence, even in those who did not have hypertension. Meanwhile, angiotensin 2 receptor blockers (ARBs) are also being evaluated, because high levels of angiotensin 2 appear to be an independent risk factor in stroke.
Brain cell stress in acute stroke results from oxygen and energy deprivation and is thought to lead to accumulation of the excitatory amino acid neurotransmitter glutamate, activation of the NMDA and other receptors to which it binds, and a massive influx of sodium and especially calcium ions. This leads to activation of Ca²+ -dependent enzymes, the generation of potentially damaging reactive molecules such as free radicals, and the initiation of programmed cell death (apoptosis), causing neuronal cell death in a relatively short time.
Many attempts have been made to influence 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 failed to show clinical benefit, perhaps partly because of inevitable delays in starting treatment, by which time damage may be irreversible.
Despite earlier disappointments, many companies have potential neuroprotectants in development, such as an inhibitor of glutamate release. There is also development of a nitrone that traps reactive oxygen radicals, and of an AMPA receptor antagonist. Another compound, a derivative of an anti-epilepsy medicine, blocks sodium and calcium channels and is being developed as an emergency treatment against stroke. Taking a different approach are research groups who are investigating a compound that modulates the activity of astrocytes – cells which surround and support nerve cells in the brain.
Companies have developed a carbamoylated form of human erythropoietin (EPO) - a modification of EPO that results in loss of haematopoietic effects but maintains the tissue protective effect. The tissue protection translates to positive effects in a number of animal models for neuronal damage including models for cerebral stroke. The molecule may offer a novel approach to a disease with few treatment options today.
Stroke prevention is also still a focus of development. Scientists have developed a new oral anticoagulant, the first since the introduction of the principle 50 years ago, as far as the clinical research phase in patients with atrial fibrillation, who are at increased risk of stroke. The new compound’s advantage lies in fixed oral dosing and simple anticoagulation monitoring.
Other thrombin inhibitors have moved to the clinical phase, as well as a monoclonal anti-Factor IX antibody. Further trials of anti-platelet medicines for stroke prevention are also continuing. The studies will also test whether addition of an angiotensin 2 receptor blocker can reduce stroke risk.
Lastly, there are new developments too in treating haemorrhagic stroke. A clotting factor preparation is tested to show evidence 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 would be a very welcome step forward.
A better understanding of the very complex process of ischaemic cell death may lead finally to a useful treatment for acute stroke, which would be a great step forward. However, prevention will remain a cornerstone in the control of this condition.
Aggressive management of hypertension and adjustments to lifestyle, such as reduction in overweight and blood lipids and an increase in regular exercise, are also essential parts of any campaign to reduce the burden of stroke in the European Union.