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Stroke. 2004;35:205-211
Published online before print December 11, 2003, doi: 10.1161/01.STR.0000106160.34316.19
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*Stroke

(Stroke. 2004;35:205.)
© 2004 American Heart Association, Inc.

Comments, Opinions, and Reviews

William M. Feinberg Lecture: Stroke Therapy in the Year 2025

Burden, Breakthroughs, and Barriers to Progress

Joseph P. Broderick, MD

From the Division of Neurology, University of Cincinnati College of Medicine, Cincinnati, Ohio.

Correspondence to Joseph P. Broderick, MD, Division of Neurology, University of Cincinnati College of Medicine, 231 Bethesda Ave, Mail Location 525, Cincinnati, OH 45242. E-mail joseph.broderick{at}uc.edu


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowThe Burden of Stroke
 down arrowReferences
 
Background— More than 700 000 strokes occurred in the United States during 2002, of which approximately 500 000 are first-ever strokes and 200 000 recurrent strokes. If we would decrease the enormous burden of stroke throughout the world, we first need to know the barriers that we have to overcome. These are quite similar to the barriers that we have tried to surmount during the last 25 years.

Stroke Prevention— We have developed many successful primary and secondary therapies to prevent stroke over the past 25 years and have begun to understand some of the genetic risk factors underlying stroke. Yet, the incidence rate of stroke in Rochester, Minn, remained unchanged from 1975 to the mid-1990s, and mortality rates for Ohio have changed little for men, women, blacks, and whites over the past decade. The primary reason that we have made little progress in decreasing the burden of stroke is that we have made little progress in modifying the primary risk factors for stroke in the population. Other barriers of improved stroke prevention in the future include costs of therapy and aging of blood vessels and brain, which is the most important risk factor for stroke.

Acute Stroke— Breakthroughs in acute stroke treatment are likely to follow the steps of cardiology with the primary focus for ischemic stroke on the restoration of oxygenated blood flow to ischemic brain as quickly as possible.To improve acute stroke therapy in the year 2025, we need to have more focused messages sent to the lay public about stroke warning signs, better and safer methods to open arteries quickly, truly effective neuroprotection in the setting of reperfusion, regional organization for acute stroke therapy, and large randomized trials to find clinically important but smaller benefits. A scientifically proven treatment for treatment of acute intracerebral hemorrhage is another major goal.

Recovery After Stroke— Brain recovery after stroke is the area of scientific discovery with the largest potential for advances far into the next century. Obstacles that block effective therapies in the recovery from stroke include the extent of initial injury from stroke, the brain plasticity of a given patient, and, most importantly, understanding the "neural code"—how the brain is organized and how cells communicate with one another.


Key Words: genetics • incidence • risk factors • stroke, acute • stroke prevention


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowThe Burden of Stroke
 down arrowReferences
 
It is a great honor to receive an award from the American Heart Association that is named after Bill Feinberg. Bill was an excellent stroke physician and researcher, but he was even a better person with a great sense of humor. In addition, my very good friend and colleague, Tom Brott, a previous Feinberg awardee, would agree that this award today really belongs to the extraordinary group of people at the University of Cincinnati College of Medicine with whom I have worked for more than 16 years.

Stroke is the third leading cause of death in the United States and the leading cause of major adult disability. To decrease the enormous burden of stroke throughout the world, we first need to know the barriers that we have to overcome. The most important barriers to successful prevention and treatment of stroke are similar to the barriers of the last 25 years. I hope to be both realistic and provocative as we look at the history and future of stroke therapy from 1975 to 2025. Data regarding the burden of stroke will be primarily from the United States since that is where we have the most information regarding long-term temporal trends in the incidence rate of stroke.


*    The Burden of Stroke
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *The Burden of Stroke
down arrowReferences
 
More than 700 000 strokes occurred in the United States during 2002, of which approximately 500 000 are first-ever strokes and 200 000 recurrent strokes. These numbers are based on the Greater Cincinnati/Northern Kentucky Stroke Study,1,2 the Rochester, Minnesota, Stroke Study,3 and the Northern Manhattan Stroke Study.4 Black Americans have nearly double the overall rate of stroke compared with white Americans, and this excess burden is particularly marked in young and middle-aged persons (Figure 1). 1



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  		Figure 1. Risk ratio for first-ever stroke in 1993–1994: blacks compared with whites. Risk ratio >1 indicates a greater risk of stroke incidence for blacks as compared with whites. GCNK indicates Greater Cincinnati/Northern Kentucky. From Kissela et al.1

What progress have we made over the past 50 years regarding the burden of stroke? The best place to answer this question is the population of Rochester, Minn, which has provided temporal trends in the incidence rates of stroke from the 1950s to the present.3,5 I first started working with the Rochester database in 1986 while a stroke fellow at the Mayo Clinic under the mentorship of Jack Whisnant. The incidence rate of stroke in the Rochester population stopped declining in the mid-1970s (Figure 2).3,5 This stabilization in rates may have been related in part to the improved identification of strokes by CT that was introduced in the mid-1970s. However, the rates of stroke in Rochester have remained stable and appear to be increasing in the most recent time periods, long after introduction of CT.



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  		Figure 2. Three-year average annual incidence rates of cerebral infarction: Rochester, Minn, 1955–1994. *Adjusted to 1990 USW population. (Used with permission from the Mayo Foundation [copyright 2003].47)

These data indicate the critical importance of past, ongoing, and future epidemiological studies of stroke incidence rates and mortality. Population studies of stroke incidence, mortality, and treatment are not "sexy" compared with finding a stroke gene, transfusing stem cells, or recanalizing an arterial clot with a mechanical device. But without surveillance data from epidemiological studies, we have no way of knowing where we have been, where we are at present, and what progress we are making in decreasing the burden of stroke by our scientific advances.

If the age-specific rates of stroke remain unchanged from 2002 to 2025, the overall number of strokes in the United States will increase from approximately 700 000 in 2002 to 1 136 000 in 2025 (Figure 3). The reason for this increase is that the percentage of the population in the oldest age groups, who have the highest stroke risk, is projected to increase substantially. Even if we stand still with regard to stroke prevention, the number of strokes will increase.



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  		Figure 3. Projected number of strokes in United States during 2002–2025.

Stroke Prevention
The development of new stroke prevention therapies over the past 25 years is impressive. For example, in 1975 we had good scientific evidence for antihypertensive therapy in primary stroke prevention6,7 and were nearing the completion of a secondary prevention study showing the effectiveness of aspirin.8 At present, we have scientific evidence concerning the effectiveness of 4 antiplatelet drugs for secondary stroke prevention,9–13 warfarin for primary and secondary stroke prevention,12–16 statins for primary stroke prevention,17–20 antihypertensive therapy for primary and secondary stroke prevention,21,22 red blood cell transfusions in sickle cell disease for primary stroke prevention,23 and carotid endarterectomy for both secondary and primary stroke prevention.24–27 Comparison of the effectiveness of carotid stenting with carotid endarterectomy is a very active area of investigation.28–31

We have excellent epidemiological evidence regarding the effectiveness of cessation of smoking for lowering the associated risk of ischemic stroke and ruptured intracranial aneurysms,32–34 as well as exercise and diet for stroke prevention.35–38

We are also beginning to amass more knowledge of genes that increase stroke risk. Some disorders, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), due to mutations in the Notch3 gene on chromosome 19,39,40 have a clear mendelian mode of inheritance, while other genetic mutations appear to act as a risk factor, such as the apolipoprotein E4 genotype and lobar intracerebral hemorrhage.41–43 Genetic risk factors may lead to stroke by affecting blood products (sickle cell disease), the endothelium (CADASIL), elastin in the blood vessel wall,44 and amyloid deposition in several components of the brain blood vessel.41–43

We even have effective treatments to prevent stroke in patients with several genetic diseases, including red blood cell transfusions for sickle cell disease and agalsidase alfa (enzyme replacement for an endothelial lysosomal enzyme) for Fabry disease.45,46

If we have developed so many successful primary and secondary therapies to prevent stroke, why has the incidence of stroke remain unchanged from 1975 to the present (Figure 2)?47 Even stroke mortality rates for Ohio have remained unchanged for men, women, blacks, and whites over the past 10 years.48 The reason that we have made little progress in decreasing the incidence rates of stroke is our failure to alter at-risk behaviors, costs of therapy, and aging of the brain vasculature and brain. Unless we can overcome these barriers, we will make little headway in achieving the goals of the American Stroke Association in reducing the burden of stroke.

Smoking rates in Ohio have not changed greatly in 16 years (Figure 4). 48 The 2 states that make up our study region, Ohio and Kentucky, have 2 of the 3 highest rates of current smoking in the United States and 2 of the lowest amounts of expenditures per resident by the state from the tobacco settlements toward public education and smoking cessation programs.



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  		Figure 4. Prevalence of current smoking in Ohio residents aged >=18 years. From Chan et al.48

Figure 5 demonstrates that the epidemic of obesity in the US has also occurred in Ohio.48 The percentage of persons with self-reported hypertension has remained unchanged in Ohio (27% in 1984 compared with 25% in 2000), although data are lacking on whether control of hypertension in Ohio residents has improved over time.48 The percentage of self-reported elevated blood cholesterol has also increased substantially, from 18% in 1987 to 32% in 2000.48 Some of this may reflect increased surveillance, but some is almost certainly related to increased obesity. In surveys of the population of Greater Cincinnati/Northern Kentucky, the percentage of diabetes and elevated cholesterol increased significantly between 1995 and 2000.49,50 Thus, we have made little progress in decreasing the burden of stroke because we have made little progress in modifying the primary risk factors for stroke in the population.



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  		Figure 5. Prevalence of overweight and obese persons in Ohio residents aged >=18 years. From Chan et al.48

Two patients with prior focal cerebral ischemia whom I saw in the office during 1 week are the basis forTable 1. Both patients, who had Medicare and had to pay for their own medications, decided to not take a second antiplatelet medicine because of cost. If a patient takes 2 antiplatelet agents (either clopidogrel or a combination of aspirin/slow-release dipyridamole), a statin, an angiotensin-converting enzyme inhibitor, and a diuretic, the total average cost per year in the United States would be more than $3600.


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  		TABLE 1. Cost of Medications for Secondary Stroke Prevention

The absolute risk reductions inTable 1 are compared with placebo except for data from the Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events (CAPRIE) Study, in which the comparison is between clopidogrel and aspirin.10,11,21 As we can see, aspirin and diuretics are cost-effective. The cost-effectiveness of other drugs for stroke prevention is less clear. Let us assume that by adding a statin, another antiplatelet drug, and an angiotensin-converting enzyme inhibitor to the current regimen of aspirin and a diuretic, the absolute risk of stroke can be reduced by an additional 1% per year. Some patients would almost certainly decide to not spend $35 000 over 10 years to additionally decrease their absolute risk of stroke by approximately 10% to 15% (or approximately 1 in 10).

We will have new therapies for genetic diseases, but the costs may be prohibitive except for the very wealthy. For example, treatment for Fabry disease (agalsidase alpha) is likely to be approved in the United States during 2003. The estimated cost will be $150 000 to $200 000 per patient per year.

Finally, the most important risk factor for stroke is older age since the incidence rate of stroke increases exponentially with advancing age.1,3 Even though other important risk factors increase with age and may be potentially modifiable, until we solve the riddle of the aging of blood vessels and brain, stroke will remain one of the great burdens of humanity.

Acute Stroke Therapy
A 62-year-old woman who was treated with combined intravenous and intra-arterial recombinant tissue plasminogen activator (tPA) illustrates several principles that are critical for acute stroke therapy now and in the year 2025 (Figure 6). First, breakthroughs in acute stroke treatment are likely to follow the steps of cardiology with the primary focus on restoration of oxygenated blood flow to ischemic brain as quickly as possible. Second, patients and their families have to immediately recognize the signs and symptoms of stroke and call the designated emergency number, as quickly as possible. Third, delivery of care must be well organized from the contact and arrival of emergency medical services to evaluation and treatment in the emergency department. Fourth, treatment of acute stroke in the future will almost certainly be multimodal and suited to fit specific patients.



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  		Figure 6. A 62-year-old woman with acute brain stem stroke. Pt indicates patient; ED, emergency department; IV, intravenous; IA, intra-arterial; and NIHSS, National Institutes of Health Stroke Scale.

We have made extraordinary progress in development of acute stroke therapies.51–60 Therapies with evidence of benefit from randomized trials include intravenous tPA within 3 hours of onset, intra-arterial prourokinase with intravenous heparin within 6 hours of onset, stroke units, and aspirin for acute ischemic stroke; nimodipine for subarachnoid hemorrhage; and coiling and clipping of intracranial aneurysms to prevent rebleeding. Currently, we have no scientifically proven treatments for intracerebral hemorrhage.61

Where is acute stroke therapy headed in 2025? Already, we have many ongoing pilot studies exploring combination therapies. These include studies of combined intravenous and intra-arterial recanalization (the Interventional Management of Stroke Study) that link the advantages of intravenous tPA (fast, widely available) with intra-arterial recanalization (possibly improved recanalization, titration of dose).56,58 Ultrasound devices that are currently in testing include intra-arterial catheters that deliver lytic drug and ultrasound at the site of the clot (EKOS MicroLysUS catheter) and machines, both traditional transcranial Doppler and experimental devices, that deliver ultrasound energy through the skull to enhance the lytic effect of tPA.62 Other recanalization devices include the Neurojet, which fragments and removes clot by generation of high-velocity jets of saline, devices that fragment clot by laser energy, and wire devices that remove clot by assuming a given shape (eg, pig’s tail, basket) after exit from the angiographic microcatheter.

In addition to mechanical devices, the future will likely include combinations of thrombolytic agents and other medications. An example of such a trial is the CLEAR Trial (Combination approach to Lysis utilizing Eptifibatide And rt-PA in acute ischemic stroke; Art Pancioli, Principal Investigator), which is just beginning. This trial is designed to compare 2 tiers of very-low-dose intravenous tPA (beginning dose of 0.3 mg/kg) and a moderate dose of eptifibatide, a glycoprotein IIb/IIIa platelet receptor blocker that is infused over 2 hours. New thrombolytic agents such as tenecteplase and desmoteplase are also in pilot testing.

If we are to be successful in improving acute stroke therapy, we must be aware of upcoming obstacles over the next 25 years. Some barriers can be changed little, if at all, and others can be modified. These obstacles include "physiological time" to restoration of blood flow, the population’s knowledge and behavior concerning warning signs of stroke, risk of recanalization therapies, access to well-organized delivery of care, and cost.

One reality that is difficult to modify is the physiological time barrier of focal ischemia. Many complaints have been voiced about the lack of concordance of animal models of acute stroke and clinical trials in humans. Yet, the agreement between the physiological time barriers in primates and clinical trials of tPA is excellent.63,64 These studies indicate that very rapid initiation of treatment and restoration of blood flow are critical.

The most modifiable barrier to acute stroke therapy is the poor knowledge of stroke warning signs among the population and the necessary behaviors to get the stroke patient to the hospital as quickly as possible. In 1995, only 57% of the population in Greater Cincinnati knew at least 1 correct warning sign when asked to name warning signs.49 In 2000, knowledge improved somewhat.50 The groups with the poorest knowledge concerning stroke warning signs are those at greatest risk: the elderly, men, and blacks.

The percentage of ischemic stroke patients who arrive at the emergency department within 2 and 3 hours of onset is low. In 1993–1994, at the time that the National Institute of Neurological Disorders and Stroke (NINDS) tPA Stroke Trial was ongoing in Greater Cincinnati, only 19% of stroke patients arrived within 2 hours.65 The percentage of stroke patients who arrived within 2 hours of stroke onset at Greater Cincinnati hospitals during 1994 is quite similar to the percentage from the 4 Coverdell pilot registry states in 2001 (J. Broderick, MD, unpublished data, 2003). Getting more patients to the hospital more rapidly represents the biggest opportunity to make a difference in acute stroke, whatever the method of recanalization. Improvement in the rapid treatment of patients with myocardial infarction over the past decade is encouraging for our efforts in stroke.66

The risk of bleeding into a damaged blood-brain barrier,67 even in the setting of very rapid recanalization, remains one of the limiting factors to widespread use of thrombolytic agents. Physicians are hesitant to use therapies with any risk, even those with substantial benefit. I believe that we will develop and test strategies over the next 25 years that will decrease this risk in the setting of recanalization.

Future success in trials of acute stroke therapy will require mobilization of the physician community as never before. Absolute differences in improvement of 11% to 13%, as in the NINDS tPA Stroke Trial, are unlikely to be repeated in future trials since this comparison was with placebo.51,68 For studies that compare new therapies with standard-dose tPA, we are more likely to see improvements in the range of 5% to 7%. Such differences will require approximately 1200 to 1500 subjects per treatment arm to adequately power these studies. Acute cardiology has already run up against a point of diminishing returns since trials with tens of thousands of subjects are needed to show very small absolute differences.

To overcome the barriers to better acute stroke therapy in the year 2025, we need to send more focused messages to the lay public about stroke warning signs and what to do when these signs are present. Patient evaluation tools used by prehospital personnel to identify stroke patients in the field can be adapted to educate the public as well (Table 2).69,70 We need better and safer methods to open arteries quickly, regional organization for acute stroke therapy, and very large randomized trials to find clinically important but smaller benefits. Neuroprotection, such as rapid hypothermia, will play an important role in restoration of blood flow, as has been shown in cardiac resuscitation.71,72 Finally, brain imaging will continue to evolve but must remain extremely fast for physicians to deliver effective therapies as soon as possible.


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  		TABLE 2. Proposed FAST Acronym for Public Education*

Brain Recovery
Acute stroke therapy will be a major focus for the next 10 to 15 years. However, as in the clinical trials of acute myocardial infarction, we will claim smaller and smaller incremental improvements as we encounter physiological barriers of focal brain ischemia. Brain recovery after stroke is the area of scientific discovery with the largest potential for advances far into the next century.

Therapies for recovery of brain function after stroke include growth factors, stimulant medications, stem and stromal cells, and new methods of physical therapy, such as restraint and robotic therapy. Many of these therapies are already in pilot trials. In addition, the use of biomechanical interfaces between neurons and silicon circuitry powering electromechanical devices is likely to play an increasingly larger role. We already have cochlear implants. It is feasible that cortical neurons in a totally paralyzed individual may someday be able to direct an electromechanical device, such as a wheelchair. In contrast, it is unlikely that we will be able to grow new cortical neurons in this same paralyzed individual that traverse the white matter, internal capsule, brain stem, and spinal cord and then synapse with appropriate spinal cord motor neurons to move the arms and legs.

Prominent barriers also block effective therapies in the recovery from stroke. These include the extent of initial injury from stroke, the brain plasticity of a given patient, and, most importantly, understanding the "neural code"—how the brain is organized and how cells communicate with one another. Ideally, we want to coax the brain of a 75-year-old stroke patient to act like the brain of a 2-year-old with minimal side effects.

Summary
In regard to primary prevention, I would like to quote Pogo, a wise individual from the newspaper comics of many years ago, who said, "We have met the enemy and he is us." Until we improve individual and group behaviors such as smoking, diet, weight control, and high blood pressure, we will make little progress with regard to decreasing the burden of stroke.

We are already in the era of combination therapy for secondary stroke prevention that includes multiple antiplatelet agents in patients for whom aspirin therapy is unsuccessful, better hypertension control, and possibly statin therapy. Other treatment modalities likely will be added to our current multipronged approach over the next 25 years. However, unless we can control the costs of medications and interventions, our scientific advances in secondary prevention will have limited impact.

Treatment of acute ischemic stroke in the year 2025 will look very much like treatment of acute myocardial infarction. Rapid recanalization of arteries by a variety of medications and devices will remain the cornerstone of therapy for ischemic stroke, and it is hoped that effective neuroprotective therapies will figure prominently as well. I predict that we will develop effective therapies for intracerebral hemorrhage.

Finally, the end of the 20th century and the beginning of the 21st century have been focused on breaking the genetic code. The 21st century and beyond will be focused on understanding the neural code. Until we know the language of brain cells and systems, our ability to restore function in the damaged or recovering brain will be limited.


*    Acknowledgments
 
Dr Broderick wishes to acknowledge the members of the Greater Cincinnati/Northern Kentucky Stroke Team at the University of Cincinnati College of Medicine.

Received July 8, 2003; revision received August 27, 2003; accepted September 10, 2003.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowThe Burden of Stroke
 *References
 

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