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Working Groups: (1) Basic Science, Drug Development, and Technology; (2) Stroke Prevention: Broadening the Approach and Intensifying the Efforts; (3) Acute Stroke Management: Applying and Expanding What We Know; (4) Brain Recovery and Rehabilitation: Harnessing the Regenerative Powers of the Brain and the Individual; (5) Into the 21st Century: The Web, Technology, and Communications: New Tools for Progress; (6) Fostering Cooperation Among Stakeholders to Enhance Stroke Care; and (7). Educating and Energizing Professionals, Patients, the Public, and Policymakers.
The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke.
Preliminary work was performed by 7 working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium.
Recommendations of the Synergium are:
To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress.
Birthdays invite reflection and planning. The journal Stroke has turned 40, providing not only an occasion to celebrate the past, but also an opportunity to help shape the future. Most of the leaders in stroke have been involved with the journal as authors, reviewers, or editors, providing an umbrella for collaboration. The participants of this synergium are leaders in the field and although the event was supported by major stroke organizations worldwide, it was a gathering of individuals interested in finding common solutions.
A result has been a Synergium, a word coined by the first author to describe a forum for working synergistically together. Seven working groups each suggested 3 main recommendations for progress that were refined during a 1-day face-to-face meeting. In addition, approximately 100 other participants and contributors from outside the synergium provided input to the final document.
More progress has been made in stroke over the past 4 decades than in the previous 4 millennia. In 1970, a landmark paper showed that hypertension was a strong risk factor for all types of stroke.1 Thereafter, other major risk factors for stroke were identified. Subsequent studies showed that many risk factors can be reduced and that their control decreases the incidence of stroke. The late 1970s saw the first proof that aspirin prevents stroke.2 This was followed by the introduction of other efficacious antiplatelet agents. The first modern comprehensive stroke unit was inaugurated in 1975,3 and tissue plasminogen activator’s effectiveness in acute stroke was demonstrated in 1995.4 Carotid endarterectomy was shown to prevent stroke in selected patients and angioplasty and stenting are currently being tested for similar purposes. Coiling offers an alternative to brain aneurysm and arterio-venous malformation surgery. Brain imaging has revolutionalized the diagnosis of stroke and the management of patients with stroke. Steady progress enhances our understanding of the mechanisms of brain injury, repair, plasticity, and recovery. Each of the previous Editors-in-Chief of Stroke (Clark Millikan, Fletcher McDowell, Henry Barnett, Oscar Rein-muth, and Mark Dyken) summarized the main developments and issues in the field during their tenures, covering the years 1970 to 2000.5–9 The developments in subsequent years have been documented in the annual “Advances” feature of Stroke.
Progress breeds paradoxes. Stroke is preventable yet is increasing globally. The same few major risk factors account for much of the leading health problems of the world but remain uncontrolled in the majority of affected individuals. Management of risk factors is the most readily applicable and affordable part of our knowledge, but prevention is neglected, and most environments are inhospitable to healthy living.
Although many advances in the understanding of excitotox-icity, neurotransmitter depletion, oxidative stress, mitochondrial failure, inflammation, and apoptosis have occurred, this has been accomplished in relative isolation from the knowledge gained on the same mechanisms that underlie other major afflictions of the brain such as Alzheimer disease, Parkinson disease, epilepsy, multiple sclerosis, and brain trauma.
Although the symptoms of stroke are well described, the majority at risk do not recognize their significance. In 1 study, only 1 in 6 individuals were aware that a treatment for stroke exists and that at the time of the study, it had to be given no more than 3 hours after symptom onset.10 In stroke, we know that time is brain, but too few brains arrive in time. Although we have learned to treat transient ischemic attack as an emergency, only approximately 1 in 8 of patients with first-time stroke have a prior transient ischemic attack.11 We must find other ways of identifying those at high risk for stroke. Subclinical (“silent”) strokes are the most common type of stroke, executive function impairment being its earliest manifestation, but this fact is barely recognized and cognition seldom measured.12
Stroke unit care improves outcomes of patients of all ages, stroke types, and severities but remains the exception rather than the rule in stroke care. The understanding of the neurobiology of brain injury, repair, and plasticity has advanced, but no histopro-tective or reparative drug has yet proved efficacious.
Stroke rehabilitation works but is largely unavailable for the time and intensity required. Effective drugs are not accessible or affordable in many developing countries nor used optimally in developed ones. Unproven, costly, or misdirected practices continue to drain resources and prevent the pursuit of more cost-effective approaches.
Although the challenges are daunting, the achievements of the past 4 decades are inspiring, having witnessed the transformation of stroke from an area notable for diagnostic precision and therapeutic impotence to a field ripe for further advances in prevention, acute treatment, and rehabilitation.
In all aspects of basic science, drug development, and technology, there is clearly a need to “do things differently” if there is to be a major advance in the development of new interventions.13,14 Over the last few years, there has been a dearth of advances that have limited genuine leaps in the understanding of the basic science and pathogenesis of stroke, and hence new targets for therapy.15,16 To counter this, a radical approach is suggested in the following areas.
There are processes that could be put in place, which may result in needs being met earlier rather than later.
In establishing the new systems described earlier, investigators will need to work in different ways. For example, sabbaticals and exchange programs and publication in completely novel areas could improve the cross-fertilization process. Mechanisms should be established that will encourage investigators by measuring the impact and novelty of their work rather than the current trend based on a researcher’s number of publications and citations. A broad platform of stroke education should provide the underpinnings for this change (see “Education” section) with a focus on national research institutions and, perhaps, the establishment of similar global institutions to cross country/cultural boundaries.
Scientific leaders around the world (organizations, institutes, and others) need to bring together these new and novel teams. Industry (eg, pharmaceuticals, biotechnology) should also be involved with a clear interface with the academic, regulatory, and government world. Government funding agencies should stimulate this new collaborative paradigm by providing funding for think tanks, which could be local, national and, even more importantly, global.
Major chronic diseases such as stroke, heart disease, cancer, Alzheimer disease and vascular cognitive impairment may be linked by common risk factors and pathophysiological mechanisms. Few simple steps like eating a balanced diet, exercising, maintaining optimal body weight, avoiding smoking, and limiting alcohol consumption can reduce risk of stroke by up to 80%.21,22 The occurrence of shared risk factors and possible common pathophysiological mechanisms (eg, inflammation, endothelial dysfunction)23 provide a backdrop for the establishment of chronic disease prevention or health preservation networks.
We propose 3 steps to influence future stroke prevention. The approach includes novel means to enhance stroke prevention and integrate strategies from within and outside the medical field with an emphasis on synergistic opportunities and collaborations.
The Chronic Disease Action Group has provided a call to action to encourage, support, and monitor activity on the implementation of evidence-based efforts to achieve global, regional, and national programs to prevent and control chronic diseases.24 This group emphasizes the control of 3 key modifiable lifestyle risks: unhealthy diet, physical inactivity, and tobacco habit. Multisectorial policies as well as long-term, sustainable action plans are encouraged to empower individuals, families, and communities to affect health-conscious behavioral change. The creation of the Global Noncommunicable Disease Network (NCDnet)25 also focuses to reduce risk, morbidity, and mortality related to 4 risk factors (tobacco use, physical inactivity, unhealthy diets, and the harmful use of alcohol). It is a global collaborative effort between the World Health Organization (WHO), member states, international partners, and other stakeholders for the prevention and control of noncommunicable diseases.
Newer approaches in the United States and some other regions may include:
The basic components of establishing a public health communication strategy include27: (a) identification of the health problem and target audience; (b) determine if the communication should be part of the intervention and, if so, strategies to best reach the audience; (c) development and testing of communication concepts, messages, and materials, including culturally appropriate messages for selected populations; (d) implementation of a health communication program based on the pretest results; and (e) assessment of the effectiveness of the messages and modification of the program accordingly. Traditional public health communication channels have included public service announcements, commercials, and newspapers, each carrying advantages and disadvantages.
The establishment of stroke units and stroke centers has been the most significant contribution to the field of acute stroke management. Stroke units are an effective intervention for the vast majority of stroke victims. Stroke centers along with prehospital system organization, access to rehabilitation, and secondary prevention improve the quality of stroke care.
Enormous lobbying to reach policymakers has been pivotal to all advances in the development of stroke care systems to date. Once “stroke” has reached political awareness, smooth implementation of care systems follows. The activities may be at the state or provincial level or even at the national level of countries such as Russia, Brazil, Spain, or the United Kingdom. The political will to improve stroke care will allow new activities in the field of stroke to be launched. Nation- or statewide documentation, standards, and quality control instruments can be implemented and more financial resources made available for the development of stroke management and prevention initiatives.
The role of physicians in initiating and guiding such developments is paramount. The achievements in the prehos-pital system in the United States and in the statewide stroke unit programs in Germany, Brazil, Spain, and Russia were only possible with the enormous input of stroke physicians. Large-scale application of the Scandinavian stroke unit model has increased access to thrombolytic therapy and reduced the case fatality rate leading to remarkable improvement in the quality of stroke care.28 This should continue to be a major source of strength and direction.
Stroke care is expensive. It has to be supported in a zero-sum game of allocation in the setting of overall shrinking budgets of general health care, an action that will be not be warmly welcomed by colleagues in other fields. A helpful and key, evidence-supported message is that improvements in stroke care frequently brings net health expenditure savings to governments by reducing rehabilitation, nursing home, and lost productivity costs.
Although capitalizing on existing therapies is well justified, flexibility has to be built into the system to facilitate the successful application of new diagnostic and therapeutic approaches. It should be possible to introduce new tools and technologies, revise protocols, and modify the composition of the stroke care team to fit the requirement of new developments in the field. By doing so, the stroke care system will remain flexible and will be amenable to incorporate advances that will continue to improve the care of the patient with stroke.
Stroke center hospitals with organized stroke unit care have made the most significant contribution to current stroke management. Efforts should be made to establish hospitals with stroke unit care in locations accessible to all patients with stroke to reduce the global burden of stroke. These specialized centers should be organized according to the local and regional needs and classified in different levels of complexity according to the available resources and treatments.29–31 The lowest tier stroke service can be built with low-cost equipment primarily focusing on well-trained interdisciplinary teams. Stroke centers should implement evidence-based treatment protocols, including thrombolytic therapy.32,33
Activating the prehospital emergency medical system and transportation to the designated stroke centers leads to a shorter delay in arrival at the hospital and better initial management. The training of ambulance teams and dispatchers in prehospital recognition of stroke as an emergency34,35 and the recognition of stroke signs increases the number of patients arriving earlier at hospital (eg, Greater Los Angeles).36 Scientific statements recommend the development of regional systems of stroke care in which ambulances bring patients with acute stroke directly to stroke center hospitals to rapidly provide approved stroke therapies, improving the outcome of patients.37
Lack of recognition of stroke signs or lack of sense of urgency to seek help by the population is a major barrier for adequate stroke treatment. Stroke awareness campaigns can increase symptom identification, thus resulting in a decrease in the time from symptom onset to hospital arrival and increase in the number of patients who may receive appropriate interventions.
A few successful examples from different parts of the world and different medical systems are described in Appendix 1 to illustrate how acute stroke treatment can be made more widely available.
After the acute period, a stroke will often affect a patient’s life for many years. During the early days to weeks after a stroke, spontaneous repair events usually lead to some degree of behavioral recovery. The neurobiology of these repair events suggests several therapeutic targets to promote further recovery. Traditional rehabilitation is one of the therapeutic tools to augment the poststroke recovery process. A wide range of repair-based therapies is also in development.38 Rehabilitation and repair is a relatively young and diverse field yet extends from the first days of inpatient care to ensuing care by rehabilitative specialists to years of chronic care in a range of settings. Current research topics span plasticity, normal learning, pharmacology, genetics, robotic engineering, occupational therapy, physical therapy, and speech therapy and growth in these areas will continue to improve rehabilitation.39
Four steps for stroke rehabilitation/recovery therapies are considered subsequently. The goal of rehabilitation/recovery stroke medicine is to have more patients achieving better recovery in the weeks after a stroke and experiencing less disability during the years that follow.
The neurobiology of spontaneous recovery and central nervous system repair40 suggests several potential therapeutic approaches that could improve patient outcome, but more research is needed. Current treatment options are limited. Although traditional rehabilitation medicine helps patients, a better understanding of its scientific basis could further increase its impact. Active research may also lead to design of new therapies that ultimately may win approval such as those using pharmacological, cell-based, electromagnetic, robotic, or neuroprosthetic approaches.
Increased basic and translational research is needed. A deeper insight into the neurobiology of poststroke recovery is required. The means by which principles of normal learning and development can be applied to stroke recovery need to be better understood.41 Tools for measuring the biology of stroke recovery in humans are needed, from behavioral measures with defined psychometric properties to biomarkers such as for recording physiology of repair-related events.42 Results of such research should be regularly compiled in both clinical and basic science State of the Art for Stroke Recovery Status Reports. This broad area of research may be best addressed by developing a group of Stroke Recovery Research Centers.
Translational studies are needed to determine the effects that various rehabilitation/repair therapies have on recovery both as isolated therapies as well as in various combinations. A number of combination approaches can be envisioned, for example, traditional rehabilitation paired with a central nervous system stimulant, brain stimulation paired with a robotic therapy (with a single computer driving both), an angiogenic growth factor followed by a synaptogenic growth factor, or exercise therapy paired with motor imagery therapy. In this regard, traditional rehabilitation can be regarded as a key tool, in the therapeutic armamentarium for stroke recovery. Like with any medical therapy, the optimal timing, intensity, duration, and content of therapy needs to be continually refined using scientifically sound approaches. Some of these issues need to be clarified for individual therapies before combining into combination therapies. Specific to stroke recovery are issues such as defining the degree of task specificity for poststroke training. The impact of comorbidi-ties, both prestroke and poststroke, needs consideration with a focus on identification of possible modifiable and nonmodi-fiable comorbidities.
Substantial data exist on the practice of poststroke rehabilitation.43 As parallel research continues to refine the approaches, there is a need to apply currently existing knowledge to optimize patient outcome. Key issues include the organizational structure, timing, intensity, and task specificity of poststroke therapy.44 Attention to community reintegration is also needed.
Detailed, standardized poststroke therapy protocols need to be developed and their practice associated with proper training. This should extend to transition to the community and then to a multiyear chronic phase of rehabilitation. Monetary and payment incentives must be redefined to drive implementation of these protocols. The lessons from published studies and best practices must be operationalized.45 This can be partly achieved by improved benchmarking of processes, outcomes, and costs.
Medical school and postgraduate training should incorporate the protocols and best practices and should include suitable educational media and modules to support the implementation. Many of these solutions can be addressed by development of Stroke Recovery Research Centers.
The best standardized measures of behavior and outcomes after stroke need to be defined and then placed into clinical practice, at the same time continuing to generate appropriate research. These need to be used across rehabilitation systems and regions. These should be measured and communicated in a consistent manner. Standardized rater training needs to be developed for these measures.
Surrogate markers of treatment effect also are needed, including imaging (anatomic and functional), physiological, and biological (such as genetics). These might be used as predictive tools for outcome and thus be of value for triage; as entry criteria in clinical trials of repair-related therapies; or in evaluating treatment outcomes to guide clinical decision-making.
Achieving consensus on clinical measures and biomarkers in this context would be useful for clinical practice and also for developing clinical trials of therapies targeting stroke recovery.
Experts need to be gathered to discuss these issues and to propose unifying strategies to achieve rapid progress in the study of rehabilitation interventions. One possible mechanism would be an International Harmonization Conference, which would help achieve expert consensus on poststroke behavioral and clinical measures as well as on surrogate markers, as has been done in other neurological conditions. Development of Stroke Recovery Research Centers would be useful to achieve such consensus, for subsequent pilot testing of the recommendations, and for defining means for broader implementation.
Further research is needed to define the psychometric qualities and performance of proposed surrogate markers.
Available research suggests many strong candidates for therapies that are likely to improve poststroke recovery by targeting repair-related processes. However, clinical trials in this domain are few and often small in size. A significant need exists to design and execute clinical trials focused on stroke rehabilitation and repair.
Stroke rehabilitation/repair clinical trials need to be hypothesis-driven, properly designed, and appropriately powered with vertical integration of basic, clinical, and epidemi-ological disciplines. The clinical trial structure should extend beyond mere hypothesis testing to discovery and exploration, the latter being much needed in this expanding field with immense potential to help numerous patients with stroke.
Randomized clinical trials are the mainstay of examining candidate therapies. Additional research structures also might be used to further address these issues. Examples include innovative trial designs such as a cluster randomized design as well as shared databases.
Note that the impact of such trials will be maximized if paralleled by studies of clinical effectiveness and pertinent health economic topics.
A Neurorecovery Consortium needs to be created consisting of academic (basic and clinical researchers, likely based at the Stroke Recovery Research Centers), industry, government research, clinicians, and payers with the mission being to define priorities and future actions for stroke recovery trials. Specific Stroke Rehabilitation/Recovery Conferences should be supported to address shared issues related to stroke recovery and rehabilitation.
Centralized strategic plans for brain recovery science should be developed, akin to the England Stroke Research Centers. Clinical trial networks should be developed to accelerate completion of stroke recovery clinical trials using cardiac disease or cancer cooperative groups as examples.
Major reductions in the burden of stroke can be achieved by providing better public education. In many parts of the world, access to reliable medical information and even electricity is limited. The electronic means to disseminate health information (eg, healthier lifestyle, risk factors, stroke symptoms, and emergency response) are available in industrialized countries, but less so in developing countries. There is a wide disparity in global internet penetration46 according to geographic (Figure) and demographic characteristics with older individuals less likely to access electronic information. Adoption of universal technology standards and worldwide unrestricted access to data will in part define how these disparities can be addressed. In the developed world, with the advent of high-bandwidth wireless delivery systems, there will be few regions without Internet access provided that sufficient resources are invested. In those parts of the world where connectivity is more limited, different strategies for knowledge dissemination and behavior change will need to be adapted to the available communication means (eg, mobile phones, print, radio, television, word of mouth).
To reduce stroke risk, electronic media-enabled tools can be used for self-assessment and motivation for self-management. These information portals can provide self-administered programs and/or interactions with professionals.
Lay organizations (eg, church, community groups) are an underused resource that can provide insights into the types of support and problem-solving that are most needed by stroke survivors, including advice on financial resources, legal matters, and social benefits. Resources should be devoted to supporting these peer-to-peer networks with interfaces to reliable sources of health information.
To be free of bias, health information should be reviewed or provided by experts in stroke in collaboration with experts in public education without conflict of interest (eg, government and nongovernment stroke-oriented health organizations) and delivered in a persuasive and understandable format consistent with principles of marketing and behavioral sciences as appropriate for the region.
Special task forces of these same organizations should prepare evidence-based online education for general practitioners, specialists, nurses, therapists, and other healthcare workers in multiple languages tailored to professional groups working in diverse surroundings. These electronic information clearinghouses should be accessible to health professionals worldwide and include interactive educational methods whenever possible. These materials should be adaptable to environments where access to electricity and electronic communications is limited. This material should also be available as a degree-based distance learning program for healthcare workers worldwide.
Communication resources and social networking tools should be tailored to support local stroke initiatives consisting of professionals, decision-makers, politicians, administrators, representatives of local industry and businesses together with lay people. All initiatives should be tailored to raise public awareness of stroke and to spread information on its prevention and management.
Evidence exists that advanced telemedicine communication technology for stroke (“telestroke”) is beneficial where immediate access to stroke expertise is not available.47–50 Telemedicine may help to provide stroke prevention, acute care, and rehabilitation services in remote regions51 and smaller urban hospitals without stroke expertise and to extend clinical research into a broader global community. In addition, more innovative rehabilitation therapies, which can be administered in areas and countries with limited resources, must be implemented to reduce inequalities of access to rehabilitation. Close collaboration of healthcare administrators, physicians, allied healthcare providers, basic scientists, and engineers is needed to develop and implement new rehabilitation paradigms.
Electronic communications between patients and professionals have an enormous potential to enhance self-management of risk factors and promote healthier lifestyles (eg, obtaining advice on medication use and adherence, prevention, follow-up laboratory test results, and medical problems through a virtual healthcare visit or an e-consultation (www.mayoclinic.org). Data management systems need to be developed to maximize the potential benefits of this emerging area and create manageable tools and actionable tasks for health-care workers.
Leaders and key stakeholders (including patients) will need to embrace these new models of telemedicine and virtual patient–provider interactions that will permit access especially for patients who are disabled or live in geographically remote regions. A first step is to reduce barriers to telemedicine-enabled practice to encourage broader access to high-quality stroke care and rapid treatment for acute stroke therapies. Development of novel technology-assisted rehabilitation methods should be encouraged.
Electronic health records are critical for quick and reliable access to patient information, for effective communication of care plans between different providers and settings, and for reducing medical errors. Furthermore, providing citizens with the option of having access to their own personal health records may enhance their adherence to treatment recommendations.
Electronic registries can help evaluate documentation of treatment practices, treatment efficacy and comparative effectiveness, and improve clinical management of patients with stroke. Registries such as Safe Implementation of Thrombolysis in Stroke [SITS]; www.acutestroke.org/) and those of Austria, Finland, Scotland, Sweden, the United Kingdom, and Japan and national quality improvement programs in the United States (www.strokeassociation.org/presenter.jhtml?identifier=3002728) have improved stroke care by providing feedback, benchmarks, and sharing of best practices. Electronic resources should be developed to support the capture and analysis of patient-reported outcomes for clinical care and research.
All nations should pursue to develop national, interoperable electronic health record systems with the goal of supporting continuity of care through delivery of comprehensive medical information on demand at the point of care for all their citizens. Common data elements pertinent to stroke-relevant risk factors, treatments, and functional outcomes should be included in the electronic health record systems. Ideally, nations should collaborate to develop international standards for data format and description to support international integration.
All nations should participate in national or international stroke quality improvement programs or registries or develop their own programs if current models are not suitable for their population or environment to provide the highest quality stroke care.
Interactions among major stakeholders in the stroke field such as large stroke organizations, government agencies, nongovernmental organizations, industry, and patient organizations can be mutually beneficial. Integrated activities among these groups can enhance patient care, the development and implementation of new therapies, and the dissemination of new and existing information. The following sections describe the activities/contributions of these 5 sectors and also provide 3 concrete suggestions of how to enhance mutually beneficial activities over the next several years.
Stroke is a prototype disease for coordinated actions vertically (with other medical disciplines) as well as horizontally by interactions among stakeholder organizations, government, and industry. Large stroke organizations such as the WSO serve as a key component in these networks, providing important leadership roles in coordinating activities and in establishing stroke firmly on the global health agenda. Improved stroke management is crucially dependent on an effective organization in all aspects of care. The large stroke organizations should establish clear policies and provide recommendations through guidelines and other documents. The large stroke organizations also organize large scientific conferences providing a platform for scientific advances and interactions. Tackling the global burden of stroke constitutes a major health challenge.
The AHA formation of the American Stroke Association (ASA) 10 years ago and its evolution to date is an excellent example of how an NGO, in this case a voluntary health organization, can influence scientific discovery and the translation of science into guidelines and how it can then implement programs to support guideline adherence, to improve outcomes, to provide extensive provider and patient resources, and to advocate for system change. AHA/ASA’s expertise as a convener of experts to develop consensus statements and guidelines, as a generator of patient and public education, and its field structure of staff and volunteers who implement its programs all contribute to its success.
Going forward organizations such as AHA/ASA and WSO will need to collaborate extensively with other large stroke organizations and nongovernmental organizations, government agencies, industry, and academia to further advancements in patient care and development of new therapies and approaches.
The National Institute of Neurological Disorders and Stroke (NINDS) is committed to the development of better therapies to prevent stroke and to improve the outcome for patients with stroke. The NINDS Stroke Program Review Group52 outlined the priority areas for research and NINDS looks forward to an exciting new era in stroke research. NINDS has a number of ongoing clinical trials that are evaluating novel prevention approaches, acute interventions, and recovery-enhancing strategies. In addition to drugs and devices, the science of behavioral change needs to target the promotion of healthy behaviors decades before the age-dependent risk of stroke starts its exponential ascent. The NINDS translational program works with and funds investigators and their industry partners to bring promising stroke therapies through preclinical development. The NINDS, however, faces a plethora of hurdles. Unfortunately, a number of important and expensive clinical stroke trials cannot be completed due to poor enrollment. A greater emphasis on Phase II studies should be considered to ensure that experimental therapies tested in rigorously conducted animal studies actually engage the intended biological target in patients.
Patient organizations range from small, informal, local support groups to large corporations with significant influence. Interactions between patient organizations and other organizations flow both ways. The purposes of these interactions are many and therefore this topic is quite complex. The triggers for interactions are generally of 3 types: (1) issues of clinical service and patient safety; (2) driving innovation and science; and (3) influencing business and healthcare economics. Patient organizations can be conduits for patients to influence healthcare organizations, government, industry, and academia. Processes may be ad hoc or organized. Actions may be taken proactively or reactively. Patient organizations can be vehicles for patients to be influenced by healthcare organizations, government, industry, and academia. Again, processes may be ad hoc or organized, and actions may be taken proactively or reactively.
Industry plays a vital role in the development and implementation of novel therapies directed at improving the prevention and treatment of stroke. Most new drug or device therapies are discovered by relevant companies or in-licensed from other sources. The company then performs the necessary preclinical steps to allow for the performance of clinical trials. Clinical trials performed by the company that demonstrate safety and efficacy of the new therapeutic agent can lead to regulatory approval, presuming an adequate data package. Industry thus provides a key link for stroke patient care, new and presumably improved therapeutic agents. Additionally, industry is an important source for the dissemination of new information about stroke to both physicians and the lay public. This task is performed by sponsorship of conferences, education seminars, and small group meetings for both professional and lay audiences. The content of these educational endeavors should be free of bias, providing balanced and educationally sound information for the intended audience.
Three specific recommendations to enhance cooperation among large stroke organizations, nongovernmental organizations, government, patient organizations, and industry are: (1) provide an appropriate mechanism for the various stakeholders to communicate with each other about their needs and goals; (2) enhance clinical research by having these entities provide input about unmet needs and how to develop and disseminate new therapies; and (3) enhance patient and physician education by jointly developing and implementing educational initiatives.
A method to achieve these recommendations and those of all aspects of this document is to establish a consensus working group of these stakeholders under the aegis of organizations such as the WSO/WFN to discuss develop and propose an overall agenda for stroke worldwide.
Detailed clinical stroke knowledge is increasingly important in Europe, North America, and other developed regions and subspecialty training focused on stroke prevention, acute care, and rehabilitation has been formalized.32,53 Stroke units have become common in developed countries. In poorer countries, especially in those classified as “low income” by the World Bank, specialized care hardly exists.54 A first step in improving stroke care globally is to improve the stroke-related education of care providers in developing countries. There are mechanisms in place for distributing knowledge and education related to HIV/AIDS, malaria, and other infectious diseases. These same models could be applied to stroke education.
Several organizations including the ASA, the ESO, and the WSO have educational and professional training web sites. For example, the WSO site is the World Stroke Academy (www.world-stroke-academy.org/). It is available globally and is free. It is endorsed and supported by other educational initiatives including those from the ASA and the ESO. Other programs such as those from the AHA/ASA (http://my.americanheart.org/professional/) and the ESO (www.stroke-university.com/) provide professional educational resources. Globally, there are insufficient numbers of physicians trained in stroke. Neurovascular Education and Training in Stroke Management and Acute Reperfusion Therapy (NET SMART) is a government-funded, evidence-based, online educational system (www.netsmart-stroke.com/) offering programs to support the learning needs of advanced practice nurses (nurse practitioners and clinical nurse specialists). Stroke-educated nurses, more numerous than physicians, are capable of playing instrumental roles within telestroke networks.55 In Europe, a downloadable eCME certificate can be obtained that is recognized by other programs such as the European Masters in Stroke Medicine (www.donau-uni.ac.at/en/studium/strokemedicine/index.php).
The WSO’s “ABC of Stroke Management” program is directed to healthcare providers in developing countries. It is being used in China, South Africa, and Vietnam and is an effective tool for postgraduate medical training.56,57 In Viet-nam, 6000 medical doctors have finished WSO-sponsored stroke training. Approaches for rapid and accurate diagnosis and the importance of prevention of complications are emphasized.58 Improving the availability of effective medications throughout the world is critical. The use of telemedicine to extend stroke expertise to underserved areas may be possible.48 The wider use of early mobilization and task-dependent rehabilitation to optimize long-term outcomes, including reintegration of patients with stroke into the family, workplace, and community, is an important goal. It is important to develop a concept of “brain health” that can be promoted for primordial and secondary prevention.
Patient and bystander responses to stroke symptoms are often delayed.59 Patient-focused voluntary organizations have developed programs to increase the stroke knowledge of the general public, patients with stroke, and their families. The AHA/ASA along with the American Academy of Neurology and the American College of Emergency Physicians (Give-Me-5), the ESO, and the Stroke Alliance for Europe (SAFE) have developed informational brochures and advertisements for this purpose. It is important to further disseminate these materials as teaching aids in schools and communities.
Step 1: Increase education directed at professionals including healthcare providers on a global scale by using on-site and website stroke teaching programs that are integrated into the medical education curricula. Recommendations should be based on a “brain health” concept that enables promotion of preventive measures. The aim is to make professional specialized care available to patients with stroke throughout the world within the next decade.
Step 2: Further develop national health education programs offered for stroke survivors and their families. These programs should be offered in schools and communities under the leadership of the scientific organizations such as the WSO, the AHA/ASA, the ESO, and other regional organizations. The aim is to improve stroke prevention and the public’s recognition and response to stroke symptoms.
Worldwide efforts to increase knowledge and concern about stroke, its prevention, treatment opportunities, and outcomes have also focused on politicians and key opinion leaders. The role of governmental policy on stroke research and care is increasingly recognized.
In the United States, advocacy efforts have largely been directed at increasing or at least sustaining funding for research supported by the NIH.60 Advocacy, in part, led to NIH Progress Review Groups aimed at identifying targets and strategies for stroke-related research. In addition, national advocacy efforts have supported cardiovascular and stroke prevention activities of the CDC. Specific targets included support of Food and Drug Administration oversight of tobacco products. Within states, advocacy has been aimed at improving the organization of the delivery of stroke-related health care.31 Individual states have established stroke task forces or legislative committees focused on stroke care issues such as assessments by emergency responders, transport of patients with stroke to the nearest appropriate hospital, identification of primary stroke centers and acute stroke treatment-capable hospitals, and the use of telemedicine. Legislation to prevent cigarette smoking in indoor public spaces has been enacted in several states.
Educating the public about stroke risk factors, prevention, and response has been challenging. Public knowledge about stroke in the United States continues to be poor, particularly in minority communities.61,62 Recently, the ASA, American College of Emergency Physicians, and American Academy of Neurology began a uniform education campaign, “Give Me 5,” aimed at improving recognition of stroke symptoms. The ASA Power to End Stroke program focuses on blacks, who have approximately twice the risk compared with white Americans. “You’re the Cure” is the AHA/ASA grassroots advocacy network. Through “You’re the Cure,” thousands of advocates can be mobilized to support specific pieces of legislation or programs affecting stroke through targeted e-mails, phone calls, and letters to relevant policymakers. Although a great deal has been accomplished, much remains to be done.
The European Parliament founded the SAFE in 2004, which includes representatives from 17 countries.63 In Eu-rope, policymakers have become engaged in the European Union by activities from the European Brain Council, the ESO jointly with the European Stroke Conference, and the SAFE movement. Topics include the promotion of awareness of stroke-related health costs64 and the large discrepancies between eastern and western Europe, including the much higher prevalence of risk factors and stroke in eastern Europe.
European specialist groups have lobbied for increased funding from the European Science Foundation and led to a European Stroke Workshop in Brussels hosted by the Euro-pean Commission. The resulting European Stroke Network links stroke research from bench to bedside.65 New initiatives (“Strike Out Stroke” 2009) address the general public as well as members of the European Parliament focusing on problems related to the use of anticoagulants for patients with stroke.
Step 3: Increase funding for public education and research supported by regional and national agencies. Continue support for advocacy aimed at improving the organization of the delivery of stroke-related health care based on evidence-based recommendations addressing gaps in the care delivery system.
Step 4: Educate and inform the general public about stroke risk factors, prevention, and response. Use best practices such as “Give Me 5,” aimed at improving recognition of stroke symptoms, the ASA’s “You’re the Cure” advocacy program and the “Strike Out Stroke” campaign in Europe.
To accelerate progress in stroke, we need to reach beyond it scientifically, conceptually, and pragmatically.
Scientifically the solutions lie beyond our limited models. All the major neurological brain diseases share common mechanisms such as inflammation, apoptosis, mitochondrial damage, oxidative stress, excitotoxicity, and neurotransmitter failure.66 By and large these mechanisms are studied in relation to individual diseases, not from a biological, evolutionary, or integrated viewpoint. A close study of the development of the nervous system may hold many clues as to how the brain repairs itself. Moreover, development and aging may to some extent be mirror images of each other. Stroke in the neonatal brain,67 children, and women68,69 has special features that need to be understood and addressed.
Our focus has been on lesions in the brain. Aging and the complex interaction of genetics, epigenetics, and environment and the occurrence of concomitant pathology render individuals’ brains unique. For example, cerebral infarcts shrink and the inflammation subsides with time. The opposite occurs experimentally in the presence of amyloid.70 Given that several common neurological conditions share the same mechanisms, a systematic approach may produce therapeutic targets that would be of benefit to more than one disease. It matters not only what lesion, but whose brain.
Conceptually we need to think not only of dramatic strokes of sudden onset, sometimes heralded by sudden losses of speech, sight, movement, or feeling, but of subclinical strokes, the most prevalent type of cerebrovascular disease identifiable by subtle cognitive dysfunction, usually a change in executive function.12 Moreover, in the elderly brain, amyloid deposition and Alzheimer lesions may coexist and at times interact with the vascular lesions.
Pragmatically we need to realize that if we are to become more effective in the diagnosis, treatment, rehabilitation, and prevention of stroke, we have to reach beyond our hospitals and clinics into the community, other disciplines, and the public and a larger part of the world.
We need to survey, systematize, and synergize what we do. We need to survey broadly, systematically, and specifically what we know of basic brain mechanisms of disease. We need to become aware of other models such as infectious diseases, which often has an integrated, epidemiological, clinical, and basic science approach.
In terms of acute care and rehabilitation, an organized approach seems to have been the key to the many advances. Although countries like Spain have a national stroke strategy and effective regional programs such as those of Catalonia71 and Madrid,72 the majority of countries do not. Stroke unit care should be considered a treatment/intervention in itself similar to any pharmacological treatment or a surgical procedure. There may well be other models such as trauma that may provide useful parallels and lessons.
Systematization and evaluation has been a key in many of the advances that have occurred in stroke in the past 4 decades. A prototype has been the randomized clinical trial, in which a hypothesis is tested according to prospectively agreed protocols, the collection of the data monitored, and the results evaluated. Randomized clinical trials are but 1 example of the more generic principles.
We need to reach beyond North America, western Europe, and Japan, where most clinical trials have been performed. Other parts of the world are creating infrastructures that make them capable of participating in clinical trials and other studies that can accelerate finding the answers to many common problems. The Extracranial–Intracranial (EC/IC) Bypass Study73 was an early example of how an international randomized clinical trial could reach an answer much more quickly than if it had been done in 1 country alone. More recently we saw the example of the first proof of tissue plasminogen activator effectiveness in stroke being demonstrated in an American study,4 whereas the extension of the time window was recently shown by a European study.74 We need to become imaginative in designing multiple types of clinical trials, from active registries to simple and more complex randomized clinical trials. The idea would be that everything that is done in relation to stroke becomes part of some evaluation. An important aspect of any evaluation is standardization with a need to make minimum common definitions of important items in a protocol so that databases can be made compatible and larger volumes of information can become available for analysis, model-building, and testing.
At the moment, we have a glut of guidelines but not enough guidance or guides.75 Most guidelines are developed on the basis of the level of evidence, but little attention is devoted to the relative impact of specific items. Not all are of equal value.76 We need to evaluate and rank the relative value of each activity in terms of return per unit investment of time, resources, or both.77 The comparative effectiveness research thus generated would improve clinical decision-making and lead to better allocation of scarce medical resources.
Stroke is no longer a disease of affluence. Approximately 87% of the 5.7 million deaths annually attributable to stroke occur in low-income and middle-income countries.78 The risk factors like hypertension, diabetes, and obesity are assuming epidemic proportions. Some 285 million people worldwide will live with diabetes in 2010, 70% of whom will live in developing countries.79 Moreover, by 2050, the population aged ≥ 60 years is expected almost to triple, increasing to 1.6 billion in the developing countries.80
The Institute of Medicine’s recent report recommends building evidence-based, locally relevant solutions by improving global collaboration among stakeholders to promote cardiovascular health in the developing world.81 Aligning chronic disease priorities with other health and development priorities has the potential to synergistically improve economic and health status.
There is much value in doing the simple things right in terms of prevention. “Death in old age is inevitable, but most deaths before old age are avoidable.”82 Hypertension is the single most powerful and prevalent risk factor for ischemic and hemorrhagic stroke and vascular cognitive impairment and yet too often it remains unrecognized or untreated. Blood pressure control has the greatest potential for stroke prevention.
The concept of “vascular health” or “brain health” needs to be promoted. Because atherosclerosis starts early in life, the preventive efforts should target children, youth, and mothers. Everyone needs to be involved at all stages of prevention with an emphasis on healthy living and creating an environment that nurtures it.
Finally, we need to synergize with vertical integration of basic sciences, clinical sciences, and population approaches. The digital age provides wonderful opportunities for integrating and evaluating all aspects of our activities.
The immediate need is to pursue specific recommendations:
We have come a long way, but we have even further to go. The progressive transformation of our field in the past 40 years, the accelerated pace of science, and the growing need for our contributions will assure that the next 4 decades will prove even more fruitful than the last.
We thank Gary Houser and his Stroke Group for expert help in organizing the Synergium. Warm thanks to Yvette Ballantyne and the AHA staff for help with the organization and registration for the Synergium. We thank the supporting organizations of the Syner-gium: AHA/ASA, World Federation of Neurology, WSO, ESO, European Stroke Conference, Canadian Stroke Network, Heart & Stroke Foundation Centre for Stroke Recovery, and Lippincott Williams & Wilkins. The views and conclusions of the synergium are that of the participants and contributors and not necessarily those of the supporting organizations.
A special thank you to Professor Michael Hennerici, Editor of Cerebrovascular Diseases and Chairman of the Scientific Program Committees of the European Stroke Conference, for his material support and spirit of cooperation exemplified by the joint and simultaneous publication of this article in the respective journals that he and the first author edit.
Mona Tiwari, research and editorial assistant, was immensely helpful in producing the final document. Thank you!
The Synergium authors appreciate the input of Drs Walter Koroshetz and Petra Kaufmann as well as the financial support of the National Institute of Neurological Disorders and Stroke.
We are grateful to Christina O’Callaghan and Drs David Cechetto, Ángel Chamorro, Lu Chuanzhen, Robert Cote, Antoni Davalos, Bart Demaerschalk, Valentin Fuster, Moira Kapral, Gian Luigi Lenzi, Mary Lewis, MingMing Ning, John W. Norris, Gustavo Saposnik, Exuperio Diez Tejedor, Danilo Toni, Peggy Vandervoort, Tony Vandervoort, and Mohammad Wasay for useful comments and stimulating discussion. We thank Jennifer Neisse, BS, of InTouch Health who contributed to the section on the development of public health communication strategies using traditional and newer strategies.
G.A.D.1 received other research support from Boehringer Ingelheim (BI) and Sanofi-Aventis; Consultant/Advisory Board for BI, Servier, Sanofi-Aventis, Bristol Myer Squibb. P.B.G. received Speakers Honoraria from BI; Consultant/Advisory Board for Bayer, Abott, Takeda. S.C.C.4* received research grant from GlaxoSmithKline (GSK) and Stem Cell Therapeutics; Consultant/Advisory Board for GSK, Stem Cell Therapeutics, Johnson and Johnson, Photothera (all significant) and Pfizer Inc, Allergan Inc, Grupo Ferrer SA (all modest). M.K.5* received Honoraria from BI, PAION AG, Servier, Forest Research Laboratories Inc, Neurobiological Technologies Inc, and Lund beck AS for participating in the Steering Committee meetings of ProFESS, PERFORM, ANCROD, and all ECASS, DIAS and CEPO trials, and for giving lectures in national and international meetings sponsored by the above mentioned companies and Sanofi-Aventis and BMS; Consultant/Advisory Board for BI, PAION AG, Servier, Forest Research Laboratories Inc, Neurobio-logical Technologies Inc, and Lund beck AS. B.E.S.1 is an employee of Novo Nordisk. K.L.F.2 received IRIS trial funding through National Institute of Neurological Disorders and Stroke (NINDS). G.J.H.2 received Speakers Honoraria from Pfizer, Sanofi-Aventis; Consultant/Advisory Board for BI, Sanofi-Aventis. J.C.M.2 participated/is currently participating in clinical trials of antidementia drugs sponsored by Elan, Eli Lilly and Company, Wyeth; Consultant/ Speaking Honoraria from AstraZeneca, Bristol-Myers Squibb, Ge-nentech, Lilly, Merck, Novartis, Pfizer, Schering Plough, Wyeth Elan. R.L.S.2 received a research grant from NINDS (Northern Manhattan Stroke Study). Y.W.2 is CEO and serves as/on Consultant/Advisory Board of InTouch Health, Goleta, Calif. G.A.F.3: payment to institution from companies undertaking stroke research including Lund beck, Mitsubishi, PAION, BI for trial related activities; payment to institution for administrative support of UK SITS database, BI; personal payment for educational lectures (modest) and advisory board (modest), BI, Lund beck. S.C.O.M.3 received lecture fees from BI. J.S.3 is employed at University of California; received research grants from National Institutes of Health (NIH); Consultant/Advisory Board of Talacris, Syquil, EV3, AGA, Brains-bok; University of California receives research grants from NIH and hundreds of industry companies; University of California has patent interest in the Merci retriever. M.M.B.4 is an employee of Pfizer Inc. P.D.4 is an employee of Duke University. L.E.4 is an employee of GSK. S.F.4 is an employee of Biotrofix, Inc and Massachusetts General Hospital (significant); has ownership interest in Biotrofix, Inc; and Consultant/Advisory Board for Pfizer, GSK, Johnson and John-son, Acorda, and Lanthers. J.K.4 is employed at University of Florida. L.H.S.5, Consultant/Advisory Board for Massachusetts Department of Public Health and Phreesia Inc. B.T.5 is employed at Southern IL Healthcare. N.W.5 is employed at Karolinska Institute. L.K. W.5 is employed at Chinese University of Hong Kong. S.P.6 is employed at the American Heart Association. V.H., W.H.3*, M.F.6*, M.B.7*, A.M.B.1, E.H.L.1, P.M.R.2, S.C.S.2, A.B.3, C.I.3, M.B.4, T.A.J.4, L.K.4, R.N.4, R.T.4, C.W.4, M.P.G.5, W.-D.H.5, O.S.5, Y.S.5, A.H.6, B.N.6, N.M.B.7, S.M.D.7, L.B.G.7, D.L.7, J.T.7, M.K.2, V.S.3, and B.D.5 have no conflicts to report.