Management of stroke and transient ischemic attack

Stroke is a major cause of death and disability. The resulting burden on society continues to grow, despite recent advances in acute stroke therapy. Thrombolysis reduces stroke morbidity but is only applicable to a small percentage of stroke patients. Acute stroke units, which allow for the greatest overall improvement in outcome, provide the best facilities for acute intervention. Despite recent advances in acute management, such as endarterectomy and anticoagulation, primary and secondary preventive measures to control stroke risk factors, along with appropriate specific interventions, are the key to reducing the overall burden of stroke.     

Thrombolysis, stroke units and other strategies for reducing acute stroke costs.

Stroke is the leading cause of long term disability and the third leading cause of death in the US. Nearly $US40.9 billion (1997 values) are spent each year on direct and indirect stroke-related costs in the US alone. Length of hospital stay, hospital overheads and nursing-related and rehabilitation costs account for the majority of stroke-related expenditures. Intravenous recombinant tissue plasminogen activator (rt-PA) therapy for patients presenting within 3 hours from onset of ischaemic stroke was shown to improve outcome at 3 months by the National Institute of Neurological Disease and Stroke (NINDS) investigators using a dosage of 0.9 mg/kg. When the NINDS rt-PA Stroke Study results were examined using a Markov model, savings of $US4 to $US5 million (1996 values) per 1000 patients treated with rt-PA were projected. These savings were predicted to result from decreases in length of hospital stay, inpatient rehabilitation and nursing home costs, increases in the number of patients discharged directly to home and improvements in quality-adjusted life-years. Furthermore, a recent meta-analysis has documented that the institution of stroke units, consisting of multidisciplinary specialised stroke teams, also decreased length of hospital stay, death and dependency. Because only a minority of patients who have a stroke are currently eligible for thrombolysis, implementation of specialised and standardised stroke care may further enhance cost benefits and improve patient outcomes.     

The impact of chronic obstructive pulmonary disease on long-term disability costs

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) as a cause of disability with subsequent costs remains poorly recognized. The small, growing body of literature on COPD shows that it is one of the leading causes of missed work.greater than asthma or diabetes. However, much less is known about the impact of COPD on long-term disability (LTD). Because the health care burden for disabled, working-age patients will fall heavily on managed care organizations, better estimates of the economic and pharmacoeconomic costs of COPD are required. We seek to improve understanding of the burden of COPD on several national LTD programs. METHODS: We reviewed occupational health and disability literature and government statistics to determine how long-term, respiratory-related disability is addressed by disability pension programs in 8 developed countries (Canada, France, Germany, Italy, Japan, Spain, the United Kingdom, and the United States). We then applied respiratory-specific disability definitions to country-specific population and pension information to estimate the potential burden of COPD on LTD insurance programs in each country. RESULTS: Comprehensive, relevant data to evaluate respiratory-related disability are lacking. Of the study countries, only the United States has explicit respiratory specific criteria for disability eligibility, which are based solely on spirometry. We estimate that the total burden of COPD in the study countries may range from 5 billion dollars to as high as 25 billion dollars per year if all persons who met U.S. eligibility criteria for respiratory-related disability were granted compensation. CONCLUSION: The potential burden of COPD on LTD programs may be large. The lack of standard criteria for respiratory-related disability may lead to underrecognition of COPD's true potential impact. Further work is needed to develop consistent and cost-effective ways to measure the impact of COPD and to assist in disability determination for COPD patients.     

The burden of coronary, cerebrovascular and peripheral arterial disease

Atherothrombosis is a potentially life-threatening generalised disease process that affects the coronary, cerebral and peripheral vasculature, with clinical manifestations including myocardial infarction, ischaemic stroke and peripheral arterial disease. Atherothrombosis represents a massive clinical and economic burden to healthcare, annually accounting for at least 22% of all deaths globally. Moreover, the prevalence of atherothrombotic disease is increasing as a result of increased longevity resulting in a larger cohort of older individuals. Stroke in particular is a major burden, and is the primary cause of adult disability, the second most important cause of dementia, and the third leading cause of death in industrialised countries. Atherothrombosis is also associated with a poor prognosis, significantly reducing life expectancy in the 60-year-old patient by 8-12 years depending on the vascular event. Moreover, this already shortened life expectancy is further and substantially reduced in patients with more than one atherothrombotic event. The economic burden of atherothrombosis is significant, particularly given its increasing prevalence, with the United States spending over US dollars 300 billion on it. There is thus a need for effective intervention to prevent or reduce mortality and morbidity. Evidence-based medicine using economics, clinical trials data, outcomes research, epidemiology and risk stratification are necessary to target treatment effectively to patients at greatest risk, in an attempt to reduce the burden of atherothrombotic disease.     

Gene therapy as a novel pharmaceutical intervention for stroke

Cerebrovascular disease is the leading cause of death and disability in Japan and most Western countries. Gene transfer techniques may be applicable to the treatment of serious types of stroke, since several experimental studies have revealed the usefulness of gene therapy in the protection of neurons, reduction of infarct size and improvement of function. Prevention of vasospasm after subarachnoid hemorrhage is one of the best candidates for vascular gene therapy. Ischemia-induced apoptosis, inflammation, and derangement of neurovascular units can be targeted by the gene transfer approach. Recent studies have shown that promotion of neurogenesis and functional recovery may also be achieved by this strategy. Furthermore, a combination of stem cell therapy with gene transfer methods may be feasible. This review describes novel approaches for the treatment of stroke using gene transfer techniques.     

The large and growing burden of stroke

Stroke is a disease with impacts ranging from death and disability, to reduced health-related quality of life and depression. To truly understand the burden of this disease we must investigate not only the mortality and prevalence of stroke, but also its incidence within populations. Stroke mortality and incidence declined rapidly during the 1980s and early 1990s; however, this trend appears to have slowed in more recent times. Despite many studies being conducted in Europe, and Australasia, there is a lack of reliable data from developing regions such as Asia and Africa. There are indications that although the mortality rate of stroke in such regions may be less than in developed countries, the simple fact that the populations are large means that the burden of stroke is considerable. Furthermore, as a result of epidemiological transition and rapid urbanization and industrialization many developing regions are exhibiting increased life expectancy, as well as changes in diet and other risk behaviors, such as smoking. This is contributing to a looming epidemic of stroke in these regions, as greater proportions of the population are now at risk of stroke. Fortunately, stroke is largely a preventable disease. The major risk factor for stroke, hypertension, can be controlled using both population-wide approaches, such as changes in the salt content of processed foods, and high-risk individual approaches, such as use of antihypertensive medications. Implementation of effective primary and secondary prevention strategies is likely to have an enormous benefit in reducing the burden of stroke, particularly in developing regions.     

Natural compounds modulate the autophagy with potential implication of stroke

Stroke is considered a leading cause of mortality and neurological disability, which puts a huge burden on individuals and the community. To date, effective therapy for stroke has been limited by its complex pathological mechanisms. Autophagy refers to an intracellular degrading process with the involvement of lysosomes. Autophagy plays a critical role in maintaining the homeostasis and survival of cells by eliminating damaged or non-essential cellular constituents. Increasing evidence support that autophagy protects neuronal cells from ischemic injury. However, under certain circumstances, autophagy activation induces cell death and aggravates ischemic brain injury. Diverse naturally derived compounds have been found to modulate autophagy and exert neuroprotection against stroke. In the present work, we have reviewed recent advances in naturally derived compounds that regulate autophagy and discussed their potential application in stroke treatment.KEY WORDS: Autophagy, Cerebral ischemia, Neuroprotection, Mitochondria, Lysosomal activation, Mitophagy, Natural compounds, Neurological disorders     

Genetics of stroke

Stroke is the second most common cause of death and the most common cause of disability in developed countries. Stroke is a multi-factorial disease caused by a combination of environmental and genetic factors. Numerous epidemiologic studies have documented a significant genetic component in the occurrence of strokes. Genes encoding products involved in lipid metabolism, thrombosis, and inflammation are believed to be potential genetic factors for stroke. Although a large group of candidate genes have been studied, most of the epidemiological results are conflicting. Studies of stroke as a monogenic disease have made huge progress, and animal models serve as an indispensable tool to dissect the complex genetics of stroke. In the present review, we provide insight into the role of in vivo stroke models for the study of stroke genetics.     

Discovery, development and effectiveness of coagulation-inhibiting drugs for stroke therapy

Introduction: Stroke is the third leading cause of death in the US and the leading cause of major disability. A large variety of drugs and new therapeutic strategies are the basis for modern stroke therapy. There is scientific evidence for the effectiveness of only a few coagulation-inhibiting drugs for stroke prevention and treatment, but a lot of clinical trials have been conducted or are ongoing in order to gain more scientific data on stroke management and therapy. Areas covered: This paper gives a general overview of modern coagulation-inhibiting drugs discovered and investigated for prevention or acute stroke therapy and offers prospects of future therapy options. Expert opinion: Without the development of more cost-effective future therapies and implementation of extended prevention programs, stroke will remain the leading cause of disability. There is still a strong need for the discovery of novel drug therapies that effectively avoid blood clotting and stroke without increasing the risk of hemorrhage.     

Therapeutic potential of TACE inhibitors in stroke

Stroke is the third leading cause of death and the leading cause of permanent disability in western countries and the incidence of stroke is expected to increase in the foreseeable future due to the ageing population. The effective treatment of stroke remains challenging due to the complexity and heterogenicity of the disease. Recombinant tissue plasminogen activator (rt-PA) is the only FDA-approved therapy for stroke during the first 3 hr after the disease onset. However the risk of hemorrhage and its narrow therapeutic window has limited its use in clinic. Inflammation has been known to play a crucial role in the induction and development of stroke and tumor necrosis factor-alpha (TNF-alpha) is a central player in the initiation of multiple inflammatory cascades. The recent success of three anti-TNF biologics in the clinic for the treatment of rheumatoid arthritis as well as other inflammatory diseases has further validated TNF159nflammation. TNF-alpha has also been shown to be associated with ischemic stroke. Anti-TNF biologics have been shown to be effective in reducing the disease symptoms in various pre-clinical stroke models. Small molecule TNF inhibitors are highly desirable due to the limitations of protein therapeutics. Tumor necrosis factor-alpha-converting enzyme (TACE) is the major sheddase of TNF-alpha and is essential for the generation of soluble, mature TNF-alpha. Thus TACE appears to be an attractive target for development of oral small molecule TNF-alpha inhibitors. This review summarizes the role of TNF-alpha in stroke and the effect of several TACE/MMP inhibitors in pre-clinical stroke models. The data strongly suggest that TACE/MMP inhibitors have great therapeutic potential and may be valuable alternatives in treating stroke in the clinic.     

Hormone replacement therapy and stroke

Stroke is the third most common cause of death in women and a major cause of disability. Stroke occurs in older age in women compared with men. High premenopausal estrogen concentrations in women are thought to be protective against stroke and cardiovascular disease. Estrogens are essential for normal reproductive function and they exert complex and diverse non reproductive actions on multiple tissues such as neuroprotective effects, vasodilatation, improved vascular reactivity, antithrombotic effects and lipid lowering effects. After menopause estrogen concentrations are depleted and in the past estrogen replacement therapy was considered as a potential protective agent against both cardiovascular disease and stroke. Although the use of hormone therapy was originally associated with a reduction in the risk of heart disease by about 50% in observational studies, the results regarding stroke have been less clear. In order to investigate the effect of hormone therapy on stroke risk, randomized controlled trials of cardio-and/or cerebrovascular-disease prevention in women with established heart disease have been designed. The Heart Estrogen-Progestin Replacement Study included stroke as secondary outcome. This study did not show any differences in myocardial infarction (MI) or coronary death (HR 0.99; 95%CI 0.80-1.22) and in stroke rate. In another study, the Women Estrogen Stroke Trial, 17 beta estradiol 1 mg/placebo was administered to women with previous ischemic stroke or transient ischaemic attack (TIA) having a mean age 71. No differences in stroke rate (RR 1.1; 95% CI 0.8-1.4) and in mortality rate (RR 1.2; 95% CI 0.8-1.8) were found, while a trend showing an increased rate of fatal strokes (RR 2.9; 95% CI 0.9-9.0) and for more severe non-fatal strokes (% patients with final National Institutes of Health Stroke Scale (NIHSS) 0-1: 19 % vs. 33%; p = 0.12) was observed. The Women's Health Initiative, a primary prevention study, where conjugated equine estrogen (CEE) plus medroxyprogesterone acetate/placebo was utilized, was stopped because of an excess in breast cancer and increased stroke rates (RR 1.4; 95% CI 1.1-1.8). Recently, a meta-analysis including 39,769 women participating in 28 trials has been published. Twelve studies were of secondary prevention and the overall stroke rate was 2%. In the hormone replacement therapy (HRT) arm there was a 29% increased rate of ischemic stroke (Number Needed to Harm, NNH:147). Furthermore, a 56% increased rate of death or dependency after stroke and a tendency of more fatal stroke were observed. Additionally, a higher stroke risk was reported in the first year of treatment. CONCLUSIONS: There seems to be no indication for hormone replacement therapy in the prevention of stroke in women. Further studies are needed to discover why estrogens have different effects on the heart and brain. Conventional risk-factors which could increase the risk of estrogen therapy need to be identified and as well as more restrictive inclusion and exclusion criteria such as coagulation parameters and intimal thickness should be adopted before new randomized trials are started.     

Treatments for stroke

Stroke is the third leading cause of death and the leading cause of disability in developed countries, yet remains a poorly treated condition. Treatments for stroke can be aimed at acutely improving blood flow or protecting brain tissue against ischaemia, enhancing stroke recovery or reducing the risk of stroke recurrence. This paper reviews each of these approaches, particularly focusing on mechanisms for which there are agents in clinical trials. There are a number of appealing neuroprotective agents in Phase II and III clinical trials. However, the majority of acute treatments are likely to suffer from a narrow therapeutic time window and hence limited patient access. Combinations of acute approaches are likely to offer the greatest benefit, but present challenges in development. Promotion of recovery following stroke offers enormous potential for successful therapeutic intervention. Excitingly, new developments in preclinical research have identified possible ways in which this may be achieved.     

The economic impact of chronic obstructive pulmonary disease

The cost burden associated with chronic bronchitis and emphysema, collectively known as chronic obstructive pulmonary disease (COPD), is large. The disease impacts not only on patients but caregivers and society as well. An estimated 16 million people in the US are currently diagnosed with COPD, the majority having chronic bronchitis. Mortality associated with this disease is on the upswing, as is its prevalence in the female population and the elderly. It is currently the fourth most common cause of death both in the US and worldwide. To date, the only proven cost-effective therapies for the disease are the cessation or prevention of smoking, which is the single most common cause of COPD, and vaccination to prevent influenza and pneumococcal infection. Hospitalisation and associated costs represent the greatest healthcare expenditures for people with the disease. Long-term oxygen therapy is also among the most costly interventions in terms of total money spent on direct medical costs for COPD treatment, although it is probably cost-effective because of its positive impact on rates of mortality. In fact, oxygen therapy is the only intervention to date that has been shown to decrease death rates due to COPD. Appropriate treatment with medication has the potential to decrease resource utilisation but does not appear to affect death rates. Similarly, pulmonary rehabilitation programs appear to benefit patients in terms of quality of life; however, long-term cost-effectiveness and effects on mortality have yet to be elucidated. Indirect costs also contribute a substantial part of the economic burden of the disease but are significantly harder to quantify.     

The economic impact of chronic obstructive pulmonary disease

The cost burden associated with chronic bronchitis and emphysema, collectively known as chronic obstructive pulmonary disease (COPD), is large. The disease impacts not only on patients but caregivers and society as well. An estimated 16 million people in the US are currently diagnosed with COPD, the majority having chronic bronchitis. Mortality associated with this disease is on the upswing, as is its prevalence in the female population and the elderly. It is currently the fourth most common cause of death both in the US and worldwide. To date, the only proven cost-effective therapies for the disease are the cessation or prevention of smoking, which is the single most common cause of COPD, and vaccination to prevent influenza and pneumococcal infection. Hospitalisation and associated costs represent the greatest healthcare expenditures for people with the disease. Long-term oxygen therapy is also among the most costly interventions in terms of total money spent on direct medical costs for COPD treatment, although it is probably cost-effective because of its positive impact on rates of mortality. In fact, oxygen therapy is the only intervention to date that has been shown to decrease death rates due to COPD. Appropriate treatment with medication has the potential to decrease resource utilisation but does not appear to affect death rates. Similarly, pulmonary rehabilitation programs appear to benefit patients in terms of quality of life; however, long-term cost-effectiveness and effects on mortality have yet to be elucidated. Indirect costs also contribute a substantial part of the economic burden of the disease but are significantly harder to quantify.     

Ischaemic stroke: acute-phase drug therapy. Mostly aspirin and heparin

(1) In the acute phase of ischaemic stroke, antiplatelet or anticoagulant treatments reduce the risk of recurrence and pulmonary embolism, but carry a risk of haemorrhagic transformation. (2) Aspirin has been tested in several placebo-controlled trials and has a positive risk-benefit balance, preventing about 5 deaths per 1000 patients with ischaemic stroke. Aspirin must be given as soon as computed tomography has ruled out intracerebral haemorrhage, unless thrombolytic treatment is planned. (3) Heparin has as many potential benefits as risks: it tends to be beneficial at low doses but harmful at high doses. Low-dose heparin therapy appears to be justified, especially for patients with emboligenic heart disease, tight carotid stenosis, or at risk of pulmonary embolism. Higher-dose heparin is only warranted for the rare patient with a high thrombotic risk. (4) Some thrombolytic drugs can reduce the frequency and severity of complications, but their use carries a high immediate risk of aggravation or death by haemorrhagic transformation. Alteplase has a somewhat positive risk-benefit balance in certain highly specific situations: for example, in some patients with persistent ischaemic stroke who are treated within three hours of onset, and without signs of severe stroke or risk factors for bleeding (high blood pressure, aspirin use). (5) Clinical trials have shown that routine use of "neuroprotective" treatments (calcium channel blockers, haemodilution, parenteral magnesium, oxygen therapy) does not reduce the risk of death or disability. (6) Arterial hypertension frequently occurs in the immediate aftermath of stroke, and then generally subsides. Few clinical trials have evaluated the use of antihypertensive drugs in this setting and there is little evidence of benefit. One trial showed that a sudden drop in blood pressure led to neurological aggravation. Antihypertensive drugs should only be used in stroke patients with severe hypertension or cardiac complications. (7) Cerebral oedema is an important cause of death after stroke: treatments (especially mannitol, mechanical ventilation and neurosurgery) have been poorly evaluated. (8) Other treatments recommended only for patients with persistent complications include oxygen therapy, antibiotics, paracetamol, insulin, and anticonvulsants. (9) A controversial meta-analysis suggested that management by a specialised multidisciplinary team reduced the mid-term risk of death and disability in comparison with management in a non specialised unit.     

Discovery,development and effectiveness of coagulation-inhibiting drugs for stroke therapy

Introduction: Stroke is the third leading cause of death in the US and the leading cause of major disability. A large variety of drugs and new therapeutic strategies are the basis for modern stroke therapy. There is scientific evidence for the effectiveness of only a few coagulation-inhibiting drugs for stroke prevention and treatment, but a lot of clinical trials have been conducted or are ongoing in order to gain more scientific data on stroke management and therapy.

Areas covered: This paper gives a general overview of modern coagulation-inhibiting drugs discovered and investigated for prevention or acute stroke therapy and offers prospects of future therapy options.

Expert opinion: Without the development of more cost-effective future therapies and implementation of extended prevention programs, stroke will remain the leading cause of disability. There is still a strong need for the discovery of novel drug therapies that effectively avoid blood clotting and stroke without increasing the risk of hemorrhage.     

Investigational anti-inflammatory agents for the treatment of ischaemic brain injury

Stroke is the third leading cause of death and the leading cause of disability in Western countries. To date, only approximately 2% of stroke patients are eligible for thrombolysis treatment with recombinant tissue plasminogen activator. The very limited options available for stroke treatment and recent disappointing clinical trials in stroke call for novel therapeutic approaches. Inflammation represents one of the key pathophysiological mechanisms for the progression of ischaemic stroke. Recent advances in preclinical models of stroke using investigational small molecular antagonists, neutralising antibodies/proteins or genetically altered gene functions against various inflammatory mediators suggest a great therapeutic potential of anti-inflammation for ischaemic stroke. The scope of the present review is to update the evidence for a role of inflammatory pathways in stroke and to summarise the investigational drugs currently available both in preclinical and clinical development for potential treatment of ischaemic stroke.     

Risk reduction strategies in ischaemic stroke : the role of antiplatelet therapy

Stroke is a common and serious disorder, and is a leading cause of disability and death in adults. Transient ischaemic attacks are now recognised as being common precursors of stroke, with a high risk of subsequent vascular events. The majority of strokes are ischaemic in origin, and are typically due to athero-thrombosis/microatheromatosis involving a large or small cerebral blood vessel or to an embolic event. Owing to the diffuse nature of atherothrombosis, these patients are at risk of ischaemic events in other vascular beds. Options for treating patients with acute ischaemic stroke are very limited; therefore prevention is a key strategy for reducing the risk of recurrent stroke and other vascular events. Treatment of risk factors such as hypertension, diabetes mellitus, smoking and obesity is an important approach for stroke prevention. Platelets are involved in the development of thrombi and emboli, making antiplatelet therapy an important preventive strategy. Antiplatelet agents are effective in preventing recurrent ischaemic stroke and other vascular ischaemic events, such as myocardial infarction and vascular death. In some cases, anticoagulants may be effective in preventing ischaemic stroke recurrence. Carotid endarterectomy can reduce stroke risk in patients with moderate- or high-grade carotid artery stenosis. Choosing the most appropriate therapy for the individual patient is key to optimising stroke prevention.     

New strategies for the prevention of stroke

1. Stroke is a major cause of disability and death worldwide. It is preferable to prevent stroke rather than to treat it and, for the prevention of stroke, all risk factors relating to stroke need to be understood. The present paper reviews potential new strategies for the prevention of stroke based on findings of new risk factors, as well as classical risk factors. 2. Recently, new risk factors related to stroke were reported, including dysfunction of the arterial baroreflex, pro‐inflammatory cytokines, vitamins and hormone deficiency. Correspondingly, therapies targeting these risk factors where shown to significantly reduce the incidence and/or severity of stroke. 3. Because the genesis of stroke is multifactorial, the prevention of stroke should not target one risk factor only. Combination therapies with drugs acting on different risk factors may be more effective in the prevention of stroke.