Current Drug Targets

ISSN: 1389-4501

Current Drug Targets
Volume 8, Number 7, July 2007

Contents

Stroke Prevention
Guest Editors: T. Tatlisumak, K. Rantanen and M. Fisher


Editorial Pp. 784-785


The Large and Growing Burden of Stroke Pp. 786-793
S.L. Paul, V.K. Srikanth and A.G. Thrift
[Abstract]


Prevention of Ischemic Stroke: Overview of Traditional Risk Factors Pp. 794-801
J.R. Romero
[Abstract]


Emerging Risk Factors for Cerebrovascular Disease Pp. 802-816
N.J. Solenski
[Abstract]


Antithrombotic Treatment in the Prevention of Ischemic Stroke Pp. 817-823
U. Emre, K. Rantanen and T. Tatlisumak
[Abstract]


Prevention of Ischemic Stroke: Antithrombotic Therapy in Cardiac Embolism Pp. 824-831
Á. Cervera, S. Amaro, V. Obach and Á. Chamorro
[Abstract]


Prevention of Intracerebral Haemorrhage Pp. 832-838
P. Mitchell, D. Mitra, B.A. Gregson and A.D. Mendelow
[Abstract]


Treatment of Leukoaraiosis: A Futuristic View Pp. 839-845
J. Helenius and T. Tatlisumak
[Abstract]


Prophylactic Neuroprotection Pp. 846-849
S.I. Savitz and M. Fisher
[Abstract]


Advancing Stroke Therapeutics Through Genetic Understanding Pp. 850-859
O.A. Ross, B.B. Worrall and J.F. Meschia
[Abstract]


Prevention of Ischemic Stroke: Surgery Pp. 860-866
K. Rajamani and S. Chaturvedi
[Abstract]


Stenting and Prevention of Ischemic Stroke Pp. 867-873
M. Mazighi and A. Abou-Chebl
[Abstract]


Systematic Review of Public Education and Policy for Stroke Prevention Pp. 874-879
D.L. Wilson, R.J. Beyth, P. Linn and P. Berger
[Abstract]




Abstracts

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Editorial: Stroke Prevention: A Challenging but Rewarding Task

Stroke is a worldwide major health problem being one of the most common killers and causes of disability in industrialized countries. Burden of stroke is likely to be similar in less developed countries as well, although precise epidemiological data lack. Approximately 80% of all strokes are ischemic. Stroke ranked as the sixth leading cause of disability-adjusted life years in 1990 and is estimated to rank fourth by the year 2020 [1]. About one-half of the stroke survivors are left with a permanent handicap. Stroke mortality has declined more than 50% among population aged 25 to 74 between 1971 and 1994 in the USA and prevalence increased by 30% during the same period in the same population [2]. The incidence of stroke is rising because life expectancy is increasing worldwide resulting in a higher proportion of elderly people and with the increasing wealth resulting in unhealthy life style changes. Approximately 700 000 strokes and 160 000 stroke-related deaths occur annually in the United States alone with over 4 million stroke survivors [3]. In addition to untimely deaths, disability, and personal suffering of the patients and their families, stroke stands for a sizable economic burden. The direct and indirect annual costs of stroke exceeded 50 billion USD in 2005. A recent population-based study showed [4] that cerebrovascular disease is already more prevalent than coronary heart disease, but this latter disease leads to more deaths than cerebrovascular disease.

Although the burden of stroke is already widely recognized and experts agree on the growth of this burden in the near future, stroke prevention is understudied and underused; stroke prevention research is unacceptably underfunded when compared with the funding addressed to diseases with similar global burden. Even some key issues remain unresolved, as reflected in the following reviews. A good example is carotid artery endarterectomy: although the first carotid endarterectomy was peerformed in the 1950’s, its indications in symptomatic patients have been clarified only a decade ago and its use in patients with an asymptomatic carotid artery stenosis is still a matter of debate. We still lack evidence-based data addressing which patients should undergo carotid artery stenting or carotid artery angioplasty.

Currently we do not know in what extent we can reduce the risk of a forthcoming stroke in an individual who is in high risk and when all preventive measures are applied timely and appropriately. For example, antiplatelet therapies alone can reduce ischemic stroke risk by 20 to 30 %; but even inhibiting every single platelet would not end up complete ischemic stroke prevention, not to mention serious bleeding complications. Combining all potentially effective treatment strategies results in much larger protection. Although yet utopistic, stroke physicians should set their aim at “no recurrence” and should not be satisfied with anything less.

Primary prevention targets the whole population or selected high-risk subpopulations before a disease emerges and aims at inhibiting the development of disease whereas secondary prevention starts from the emergence of a disease and aims at preventing recurrence. The three mainstream targets in stroke prevention are 1) detection and modification of risk factors, 2) antiplatelet and anticoagulant medication for selected groups of ischemic stroke patients, and 3) surgical interventions including invasive procedures such as stenting of stenosed arteries or coiling aneurysms and vascular malformations.

Primary preventive measures include public health policies combating smoking, illicit drug use, and alcoholism. Policies tackling with obesity and food consuming habits, adding necessary exercise to routine life habits will not only reduce stroke incidence, but as well they will reduce the burden of several major diseases including coronary heart disease, hypertension, diabetes mellitus, and hyperlipidemia, just to name a few.

Stroke prevention is not only about developing high-tech therapies, but we recognize that a chain of health delivery for stroke patients should be constructed starting from primary prevention, delivering correct and timely secondary preventive measures, and incorporate measures which ensure that patients continue on these measures lifelong after discharge from hospitals. A major problem which has not yet been dealt with extensively, is the compliance of patients. Although more and more effective therapies have been developed for major stroke risk factors, many patients stop taking their medications at some time point. Arterial blood pressure, blood glucose or cholesterol levels are within the consented ranges in only a fraction of patients. Many patients stop smoking and change their life habits following an acute stroke, but return back to previous life styles shortly after their condition improves. This issue awaits innovative approaches.

Recent reports advocate a strategy of delivering health care as quickly as possible, preferably on an emergency care basis, for transient ischemic attacks and minor strokes. Patients with transient ischemic attacks are under a risk of over 10% for developing an ischemic stroke within the next 3 months [5]. Preventive measures should immediately be started in hospital and measures should be taken to confirm that patients continue on adequate preventive therapies for long periods.

As new therapies emerge that are more effective and safer, debate follows. Debates are part of progression and are most welcome. Where there is nothing new, hardly any debate is necessary. Among the most debatable issues in stroke prevention are selection of antiplatelet agents, surgery for asymptomatic carotid stenosis, and extracranial-intracranial bypass operations. We certainly need more evidence-based data for optimizing stroke prevention. Many such trials are under way and will shed more light on several aspects, still, as some issues are solved, many new will appear. We are aware that we are living in an era where things will always be “under construction”. Where evidence-based data are not available, a consensus of experts should be sought and adapted to the clinical practice. Many world-recognized experts have meritoriously reviewed most debatable issues in this special issue of “Stroke Prevention” of the Journal and delivered clear personal opinions on most hot topics in stroke prevention.

We previously have reviewed the secondary prevention of ischemic stroke in this journal [6]. Now, in this issue with the contributions of several leading experts in the stroke prevention field, we have the opportunity to extend this issue to deal with all major facades of stroke prevention. We sincerely thank all authors for the state-of-the-art reviews they provided. Our special thanks go to Editor-in-chief Professor Francis Castellino who has provided for the opportunity to us editing this special issue on stroke prevention putting stroke at the correct perspective in the priority list of this journal.

Lastly, stroke prevention is a challenging task but we have taken great steps. Aspirin was tested all along the 1980’s and now is part of our routine clinical practice. Furthermore, we have several other antiplatelet agents to choose from. We now have effective and mostly safe/well-tolerated drugs for many stroke risk factors. Stenting is currently arriving to clinical practice. Vascular malformations and aneurysms can now be treated less invasively. We have reasons to be proud, but need to work even harder. Preventionist’s motto is “zero tolerance”.


REFERENCES
[1] Sacco, R.L.; Wolf, P.A.; Gorelick, P.B. (1999) Neurology, 53 (suppl 7), S15-S24.

[2] Muntner, P.; Garrett, E.; Klag, M.; Coresh, J. (2002) Stroke, 33,1209-1213.

[3] American Heart Association. Heart Disease and Stroke Statistics-2005 Update. 2005. Dallas, Texas, USA. American Heart Association, (2005).

[4] Rothwell, P.M.; Coull, A.J.; Silver, L.E.; Fairhead, J.F.; Giles, M.F.; Lovelock, C.E.; Redgrave, J.N.E.; Bull, L.M.; Welch, S.J.V.; Cuthbertson, F.C.; Binney, L.E.; Gutnikov, S.A.; Anslow, P.; Banning, A.P.; Mant, D.; Mehta, Z. (2005) Lancet, 366,1773-1783.

[5] Johnston, S.C.; Gress, D.R.; Browner, W.S.; Sidney, S. (2000) JAMA, 284, 2901-2906.

[6] Rantanen, K.; Tatlisumak, T. (2004) Curr Drug Targets, 5, 457-472.


Turgut Tatlisumak
Kirsi Rantanen
Department of Neurology
Helsinki University Central Hospital
Helsinki
Finland


Marc Fisher
Department of Neurology
University of Massachusetts Medical School
Worcester, Massachusetts
USA


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The Large and Growing Burden of Stroke
S.L. Paul, V.K. Srikanth and A.G. Thrift

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.


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Prevention of Ischemic Stroke: Overview of Traditional Risk Factors
J.R. Romero

Stroke prevails as a common and devastating disease. Epidemiological studies have advanced our understanding of stroke risk factors and clinical trials have demonstrated effective interventions to decrease stroke risk by modifying risk factors. Stroke risk factors are classified as traditional and novel and may be further divided into modifiable and non-modifiable. In this review we discuss select traditional risk factors for ischemic stroke, interventions for primary and secondary prevention and areas of research progress. Stroke treatment should be comprehensive, involving patient, community and medical personnel education, evaluation of individual risk factors and overall stroke risk assessment. Ongoing research is exploring further interventions in the management of traditional risk factors. Future research will expand our knowledge about the contribution of genetic factors to stroke, their interaction with environmental factors and open exciting avenues for the development of new therapies.


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Emerging Risk Factors for Cerebrovascular Disease
N.J. Solenski

Nontraditional risk factors for cerebrovascular disease are rapidly emerging. The categories are expanding, and include those related to infection, inflammation, sleep disorders, hemostasis, nutrition, endocrine, and one’s individual genotype. Many of the promising factors lack large randomized prospective population studies confirming direct cause and effect. However there have been strong evidence supporting increased stroke risk factor for infection, obstructive sleep disorders, the metabolic syndrome and impaired glucose tolerance in particular. Unique drug targets have already been identified in some of these emerging risk factors. The complexity of the pathophysiology of this disease remains a challenge. For example despite repeated evidence of estrogen-related neuroprotection, large population-based studies in postmenopausal women receiving estrogen replacement did not demonstrate the expected neuroprotection. This suggests that aggressive research both at the basic science and transitional level needs to evolve, to ensure targeted successful stroke therapy. The advent of nanotechnology including the development of targeted therapeutic nanospheres, and of revolutionary molecular technology resulting in the synthesis of specific peptide mimetics, bodes well for the future development of cerebrovascular drug treatment.


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Antithrombotic Treatment in the Prevention of Ischemic Stroke
U. Emre, K. Rantanen and T. Tatlisumak

Approximately 5.7 million people died from stroke in 2005 [1]. According to World Health Organization estimates, figures are predicted to increase to 23 million first-ever strokes, 77 million stroke survivors, 61 million disability adjusted life years (DALYs) and 7.8 million deaths in the next 20 years [2]. Heart disease and stroke are leading causes of DALYs lost and deaths worldwide [3]. Over 70 % of ischemic strokes are first events, which makes primary prevention immensely important. The treatments for acute ischemic stroke have emerged during the last decade and there is growing evidence of efficacy and importance of secondary prevention. We foresee that patients at high risk of vascular events could reduce their risk by 75 to 80 % through optimal prevention strategies including a combination of lifestyle changes and medical therapy [4]. In this review, we will focus on the aspects of antithrombotic treatment of ischemic stroke (IS) in the primary and secondary prevention.


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Prevention of Ischemic Stroke: Antithrombotic Therapy in Cardiac Embolism
Á. Cervera, S. Amaro, V. Obach and Á. Chamorro

Ischemic stroke secondary to cardiac disease accounts for approximately 30% of all stroke subtypes and it may be due to a large list of conditions. Stroke secondary to heart disease causes more severe deficits, higher mortality, and increased costs that other stroke subtypes. Therefore, proper identification of cardioembolic stroke is crucial for adequate selection of optimal preventive strategies. Identification of stroke prone individuals with heart disease could also have an important therapeutic impact. This manuscript reviews the interaction between the heart and brain with a particularly emphasis in the current state of older and newer antithrombotic drugs for stroke prevention in patients with atrial fibrillation. Other neuro-cardiological issues reviewed include current antithrombotic strategies in patients with a host of heart conditions which include pacemakers, acute myocardial infarction, congestive heart failure, cardiac procedures, patent foramen ovale, valve disease, endocarditis, or cardiac tumours.


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Prevention of Intracerebral Haemorrhage
P. Mitchell, D. Mitra, B.A. Gregson and A.D. Mendelow

Nontraumatic intracerebral haemorrhages arise from a wide range of causes falling into two broad groups: discreet vascular “ictohaemorrhagic” lesions such as aneurysms, arteriovenous malformations, cavernomas, tumours, and dural fistulae; and more generalised amyloid or hypertension related conditions.

It is now possible using family history, associated risk factors and gradient echo MRI to predict cases at high risk of hypertensive or amy-loid related haemorrhage. There is considerable potential for prevention of hypertensive haemorrhages by treatment of high risk cases with antihypertensive medication. As yet no effective preventative treatment for amyloid angiopathy related ICH has emerged although a variety of drugs are under investigation.

Prevention of haemorrhage from ictohaemorrhagic lesions revolves around removal or obliteration of the lesion. Although there is a wide range of such lesions available treatments come down to three modalities. These are surgical excision, stereotactic radiosurgery and endovascular embolisation.


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Treatment of Leukoaraiosis: A Futuristic View
J. Helenius and T. Tatlisumak

Leukoaraiosis (LA or white matter changes of the brain) is a common finding on brain imaging studies in the elderly people. LA predisposes to dementia, ischemic stroke, intracerebral hemorrhage, and cognitive decline as well as associates with a significant increase in falls and gait disorders. As population ages, the incidence of LA increases and is becoming a major global health problem. Therefore, strategies for its prevention and management are urgently needed. This review includes basic knowledge on the pathophysiology, patterns of clinical presentation, risk factors, and imaging findings of LA. The very last and the most comprehensive part of this review discusses potential therapeutic approaches of the future.


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Prophylactic Neuroprotection
S.I. Savitz and M. Fisher

Ischemic brain injury can be anticipated in a number of clinical settings such as procedures associated with a high-risk for stroke, patients with transient ischemic attacks or minor strokes who are at substantial risk for early recurrence and patients with multiple vascular risk factors with an enhanced risk for ischemic stroke over many years. In such high-risk settings, it may be possible to employ neuroprotective drugs prophylactically to reduce the extent and clinical consequences of ischemic events. The concept of prophylactic neuroprotection can be envisioned for varying time periods and with a variety of drug classes depending upon the target population. This review will focus on which target populations should be considered for prophylactic neuroprotection trials and which drugs might be used in such trials.


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Advancing Stroke Therapeutics Through Genetic Understanding
O.A. Ross, B.B. Worrall and J.F. Meschia

Stroke is a complex neurological disorder that most likely results from an intricate interplay between lifestyle, environment and genetics. Genes can influence susceptibility to stroke, alter responses to pharmacotherapy, and affect disease outcome. Recently, common variations within the PDE4D and ALOX5AP genes have been identified that increase population-attributable risk of stroke in Iceland. These genes are yet to be unequivocally confirmed and the functional variants identified. Characterizing the genetic profile of individuals at highest risk of stroke will permit more targeted pharmacological approaches to early primary and secondary stroke prevention. Pharmacogenomics is likely to be particularly important for stroke prevention because of the narrow therapeutic index for treatments like warfarin that prevents thrombosis but also promotes hemorrhage. Identifying possible genetic determinants of outcome will also open new avenues of research into stroke therapeutics beyond thrombolysis.


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Prevention of Ischemic Stroke: Surgery
K. Rajamani and S. Chaturvedi

The last 15 years have witnessed a resurgence of the role of surgical options for prevention of ischemic stroke. The landmark randomized trials including NASCET and ECST were published and explored the role of carotid endarterectomy in this regard. Patients with high grade stenosis of the internal carotid artery ( ≥ 70%) with prior TIA or minor non disabling stroke in the same territory were shown to have significant benefit of the procedure compared to best medical treatment. Benefit was comparatively less in patients with moderate grade stenosis of the ICA (50-69%). Surgical treatment of patients with <50% stenosis of the ICA resulted in worse outcomes compared to medical therapy and is consequently not recommended. These studies also standardized the method for measuring the degree of ICA stenosis. The ACAS and ACST studies attempted to resolve the rather vexing issue of surgical treatment of patients with asymptomatic ICA stenosis. The risk benefit ratio in asymptomatic patients is low and depends to a large extent on a low perioperative complication rate. Studies have also attempted to identify the best medical treatment in the perioperative period during CEA. Low dose aspirin has been shown to be beneficial, but the role of statins and betablockers is promising but yet uncertain. Ischemic stroke is a common complication after CABG. In this regard surgeons have differed in their approaches to performing CEA, some preferring to do it during the bypass surgery, while others prefer a two staged procedure. The surgical treatment of complete carotid occlusion by EC-IC bypass surgery has also enjoyed renewed interest and results of the COSS study are awaited keenly. The EC-IC bypass surgical procedure is also beneficial in moya-moya disease.


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Stenting and Prevention of Ischemic Stroke
M. Mazighi and A. Abou-Chebl

Stenting for the prevention of atherosclerosis related ischemic strokes is a recent option in the therapeutic armamentarium. For extracranial carotid artery stenosis, stenting has proven its benefit in patients defined as “high-risk” for surgery, but beyond this specific population, surgery remains the gold standard. Based on recent prospective randomized trials, carotid endarterectomy (CEA) and carotid artery stenting (CAS) seem to share equivalent peri-procedural stroke risks, but the significantly higher rates of local nerve injury and myocardial infarction related to the surgical approach should favor the endovascular intervention in the future. In other locations, such as extracranial vertebral artery or intracranial stenoses, the current practice of care is not defined and the benefit of stenting is under investigation. However, in patients with symptomatic lesions despite appropriate antithrombotic therapy, stenting is considered to have a better benefit/risk profile in comparison to intracranial bypass surgery. In-stent restenosis (ISR), a major concern after stenting in coronary arteries, is an infrequent event following cervical internal carotid stenting but is relatively common and may worsen outcomes following treatment of extracranial vertebral and intracranial arterial stenoses. Drug eluting stents have proven their efficacy to control ISR and have changed dramatically the landscape of interventional cardiology, for this purpose their evaluation is now starting in the cerebral vasculature. The field of endovascular interventions is rapidly evolving and the development of devices dedicated to the cerebral vasculature is without any doubt going to extend the spectrum of treatable lesions.


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Systematic Review of Public Education and Policy for Stroke Prevention
D.L. Wilson, R.J. Beyth, P. Linn and P. Berger

Introduction: Stroke is a leading cause of disability and death around the world. Methods: We conducted a systematic review of peer reviewed articles published since 1999 on the topics of public education and policy for stroke prevention. A research librarian conducted the search using Pubmed and the International Pharmacy Abstracts (IPA). We reviewed the abstracts from the search results to determine if they met the inclusion criteria. Then we abstracted the relevant data from the articles using an evaluation criteria and data abstraction instrument. Results: The searches of Pubmed and the IPA returned 446 articles, of which 36 were included in the review. Thirty-two were educational programs and four were policies. Twenty-two of the programs were directed at patients, four at providers, and seven at both. Seven of the educational programs were judged successful using the evaluation criteria. They included two large scale programs and five narrowly targeted programs. The policies included two articles presenting guidelines for treatment for stroke prevention in specific patient populations and two articles presenting recommendations for changes in systems of care for stroke prevention and treatment. Conclusions: Future efforts to evaluate these programs will require global efforts with a special emphasis on testing and validating with international patient populations. Barriers remain for translating stroke prevention policies into clinical practice.

"This material is based upon work supported by the North Florida/South Georgia Veterans Health System, the Office of Research and Development, Rehabilitation R&D Service, and Health Services R&D Service, Department of Veteran Affairs."