Slide Lecture with Audio
This activity is based on a 45-minute slide lecture presented by Dr. Mark J. Alberts. This program is available as read only and with accompanying audio.
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Slide 1: Hello. Welcome to "Expert Discussion of the Evidence for Secondary Stroke Prevention and Management." This activity is jointly sponsored by Professional Resources in Management Education (PRIME) and Princeton CME, and is supported by an educational grant from Boehringer-Ingelheim.
My name is Mark J. Alberts, Professor of Neurology at Northwestern University Medical School, and Director of the Stroke Program at Northwestern Memorial Hospital in Chicago, Illinois. I will be your presenter.
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Slide 3: Please remember that to receive continuing education credit following the conclusion of this activity, each participant must complete the posttest and evaluation form. These forms can be easily completed online for immediate receipt of credit at www.princetoncme.com.
Thank you again for joining us. This presentation is important to managed healthcare professionals because, number one, stroke is a common and serious disease; number two, it has a significant public health financial and social burden; and number three, the best way to treat stroke is to prevent stroke. So anything we can do to optimize or augment stroke prevention will have significant public health effects.
Slide 4: Now, let us move on to our case presentation. This patient is named Hilda F. She is a 79-year-old female, who presents to her primary care physician for follow-up. Three weeks ago she suffered a deep right hemispheric lacunar stroke that left her with residual left-sided weakness. Before that she rarely visited her physician. She is a smoker of about 1 pack of cigarettes per day for the past 58 years. She also has a history of arthritis. During her hospitalization, she was found to have hypertension, diabetes, and hyperlipidemia, so she has a lot of significant medical conditions that increase her risk for having a first and recurrent stroke. Upon discharge, she was prescribed various medications for these conditions, but unfortunately she never filled these prescriptions.
Slide 5: The next slide talks about her examination. Her blood pressure is elevated at 150/90 and her pulse is 70. She has mild residual left-sided hemiparesis. Laboratory studies revealed a fasting total cholesterol of 280, which is high, an LDL cholesterol of 165, also elevated, and a glucose of 200. Prior to her stroke, Hilda was taking no medications except for 2 aspirin tablets per day for her arthritis.
Slide 6: Now, on the next slide, let us talk about a definition of stroke. There are really 2 different types of strokes, ischemic stroke and hemorrhagic stroke. Ischemic stroke is due to occlusion of a blood vessel in or around the brain, which deprives that brain territory of necessary oxygen and glucose for the nerve cells and other cells to survive. Ischemic stroke is commonly due to atherosclerosis with thrombosis, embolism, or sometimes systemic hypoperfusion.
The second type of stroke is a hemorrhagic stroke. This is when a blood vessel in or around the brain ruptures. The 2 most common varieties of hemorrhagic stroke are intracerebral hemorrhage, when a blood vessel within the blood brain ruptures, and subarachnoid hemorrhage, when a blood vessel, typically at the base of the brain, ruptures.
As we said, ischemic strokes are the most common, accounting for 85% to 87% of all strokes, and hemorrhagic strokes account for about 13% to15%. The 30-day mortality of ischemic stroke is about 8% to12% and that of hemorrhagic stroke can be up to almost 40%. So even though ischemic strokes are more common, they are less deadly; hemorrhagic strokes are less common, but they are more deadly.
Slide 7: On our next slide we talk about the epidemiology of stroke in the United States based on recent statistics from the American Heart Association. The prevalence is thought to be about 5.7 million. The incidence of stroke shows that about 700,000 Americans are thought to have a new or recurrent stroke each year in the United States. Again, the vast majority of the strokes are ischemic. A smaller percent are hemorrhagic. Out of those patients who have a stroke, about 500,000 have a first stroke and about 200,000 or 250,000 have a recurrent stroke. About 80% to 85% of patients survive a first stroke, but between 5% and 15% of them will have a recurrent stroke within 1 year.
In addition, stroke is the third most common cause of death in the United States, with about 150,000 people dying from a stroke, and again, more women die of a stroke than men; about 61% of the deaths after a stroke are seen in women, and 39% in men. And in fact, 1 of every 16 deaths in the country is due to a stroke. So again, stroke is common, and it is deadly.
Slide 8: The next slide talks about the geography of stroke. As you can see from the slide, stroke is not equally distributed throughout the United States. The southeastern part of the country is called the “stroke belt.” This is because it has the highest incidence and mortality of stroke in the entire country. What causes the stroke belt? Well, we have part of the answer. Part of this is due to the demographics of the stroke belt, risk factors, and other identifiable etiologies, but about 20% to 30% of the attributable risk in the stroke belt really remains undefined and we are not sure whether it is genetic, environmental, or something in the water. So again, we understand a lot about the stroke belt, but not all that we need to understand.
Slide 9: What about the burden of stroke? As you can see from the next slide, stroke is the leading cause of serious long-term disability in the United States. Of those people who survive a stroke, about 50% will be left with the hemiparesis, about ? will not be able to walk without assistance and about ¼ will rely on another person for their activities of daily living. In fact, a lot of stroke patients end up in nursing homes and rehabilitation because of the disability following their stroke.
Slide 10: What about the estimated cost of stroke? Well, as you can see from the next slide, stroke is an exceedingly expensive disease with total costs in the United States of about $63 billion, that's with a B, $63 billion per year. About 62% of those costs are directly related to the stroke in terms of medical care, hospitalization, medications, and the like, but well over ?, about 38%, are indirect costs (things like lost wages, caregivers having to miss work, and the like). Now, an estimate from the year 2005 to the year 2050 shows that in the United States, stroke is expected cost $2.2 trillion, if not more than that, and this is largely because of an aging population. As the baby boomers get older, their risk of having a stroke goes up fairly dramatically, and those strokes in those patients are going to cost a lot of money to take care of. So again, emphasizing the importance of primary and secondary prevention to reduce this burden of stroke, particularly in the future.
Slide 11: The next slide does talk about cost of stroke in terms of various aspects. You can see on the left-hand side, we talk about some of the inpatient costs, such as ambulance, hospitalization of about $12,400/year, rehabilitation almost $26,000/year, various therapies and devices in home health more than $3000/year. On the right-hand side of the slide, you can see some of the medication costs. At the top with aspirin combined with sustained-release dipyridamole costing about $1500/year; aspirin by itself, only $8/year; clopidogrel, $1500/year. But these costs are very small, some would say almost insignificant compared to the cost at the bottom of the table on the right-hand side of your slide. Informal care costs more than $4000/year; earnings lost almost $23,000/year, and if a patient ends up in a nursing home, you are looking at annual costs of more than $33,000. So, I would submit to you that the cost of the various medications that we may use for secondary stroke prevention, be they antiplatelet agents, an ACE inhibitor or a statin agent are really quite small and almost insignificant when you look at the cost of having a first or a recurrent stroke.
Slide 12: The next slide talks about some stroke risk factors, and many of these stroke risk factors are fortunately modifiable, things like hypertension, heart disease, atrial fibrillation, carotid stenosis, lipid disorders, diabetes, smoking, alcohol abuse, inactivity, obesity, and the like. We can do something about many of these disorders, be it through lifestyle changes, medications, surgery, or endovascular. We have opportunities to intervene and treat a lot of these modifiable risk factors.
On the right-hand side, you can see that there are, however, a number of nonmodifiable risk factors, such as aging. A few minutes ago we talked about the significant aging of the baby boomers, and how this may, in fact, drive an upcoming stroke epidemic. Men may have a higher risk of stroke than women, although women have a higher prevalence. The risk of stroke is not the same throughout all races and ethnicities. Blacks have a higher risk of stroke than whites, and Hispanics have a higher risk of stroke than whites, and lastly, we get into the genetic factors. So, clearly there is not much we can do about the nonmodifiable factors, but that makes us focus even more on aggressive treatment of the modifiable risk factors.
Slide 13: Now, before somebody has a stroke they may, in some cases, have a TIA, or a transient ischemic attack. The classic definition of a TIA is a brief episode of focal neurologic dysfunction involving the brain or the eye with clinical symptoms lasting less than 24 hours. But the new definition is going to change this, saying that the clinical symptoms typically should last less than 1 hour, and without evidence of infarction on brain imaging studies such as an MRI with diffusion weighted imaging. The reason for this change is that several well-done studies over the past few years have shown us that patients who have significant symptoms of a stroke that may last 2, 3, 4, 5 hours yet clear up, on imaging studies like a brain MRI, many of them have clear evidence of focal brain infarction (i.e., they have had a small stroke), it is just that their symptoms have resolved within 24 hours. So, because they have evidence of brain infarction on the imaging studies we think that those folks should be reclassified as having a stroke and not a TIA. So that is why the proposed new definition will emphasize that these spells should be brief and there should not be any brain imaging evidence of brain infarction to be called a real TIA.
At the bottom of the slide, you can see some of the symptoms and signs of a TIA or stroke, emphasizing the sudden onset of focal neurologic impairment, such as paresthesias, weakness, confusion, dysarthria, difficulty with walking or talking, loss of balance, coordination, or very severe headaches with no known cause. The point I think we are trying to get across with this new definition of a TIA is that a TIA signifies something serious, something bad going on in the brain, going on in the brain vasculature, and we need to treat the patients very aggressively, identifying and treating their risk factors and starting them on an antiplatelet agent.
Slide 14: There was a nice study done in England called the Oxfordshire TIA study, where they addressed the 7-day risk of having a stroke after a TIA and they were able to put together a scoring system that included key measures of age, blood pressure, clinical features, and duration. And what they found through, again, this scoring system, is that folks with a low what they called an ABCD score, age, blood pressure, clinical features and duration, (obviously, the older you are, the higher your blood pressure), if you had clinical features like weakness or speech disturbance, and if you had a duration of the event that was more than an hour, that gave you a high ABCD score, and those folks had more than a 30% risk of having a stroke, whereas those patients with an ABCD score of 0, 1, 2, or 3 had a very low risk of having a stroke in the next 7 days. So, in our clinical practice we have actually found this to be a useful tool, not necessarily by itself but combined with the overall clinical picture, the clinical scenario, laboratory results, patient history, and the like, to help us triage for which of those patients with TIA-like symptoms need to be treated more aggressively than others. It is not perfect, but I think it is one helpful tool.
Slide 15: What about the acute management of stroke? Well, obviously when someone comes in with symptoms of a stroke, we want to make sure that their basic vital signs are stabilized, such as their airway, breathing, circulation, and pulse. We want to do a brain imaging study to see if they have had a hemorrhagic stroke or presumed ischemic stroke. If it is an ischemic stroke and it is within a few hours, we want to consider them for thrombolytic therapy with intravenous alteplase, or tPA. We want to use antithrombotic agents, both acutely and long-term, to reduce the risk of having a new or recurrent stroke. If they have to be in bed for an extended period of time, we want to use DVT prophylaxis to prevent the formation of DVT. We want to manage their blood pressure, although this remains somewhat controversial. Certainly, if the blood pressure is greater than 220/120 we do want to gently reduce it by about 15% to 20%. The recent acute ischemic stroke guidelines were published in Stroke just a few months ago. Harold Adams was the first author of that. He suggested that if the patient is stable after 24 hours and their symptoms have been fairly constant or improving, and they do not have a high-grade stenosis of the carotid or basilar artery that may have led to this event or admission, then it may be okay to gently introduce or reintroduce some blood pressure medications, again, not with the goal of getting their blood pressure down to 120/80 in the next 24 hours, but at least starting them on something perhaps gently to address their blood pressure issues, so that, again, when they leave the hospital, at least they are taking some blood pressure medications, but this requires, again, a lot of caution and judgment.
In terms of glycemic management, we know from numerous studies that those patients with strokes and elevated blood sugars tend to do poorly, despite one negative study from the United Kingdom published several months ago. That study, in my opinion, had some significant flaws. Most people in the United States are still aggressively treating stroke patients with elevated blood sugars, particularly if the blood sugars are more than 140 or 150 with insulin, and in some cases, we are using an insulin drip in the hospital in the ICU or the stroke unit.
Slide 16: The next slide talks about guidelines for secondary prevention of patients who have had an ischemic stroke or a TIA, and obviously there are some things we can do that do not involve medications: lifestyle modifications, healthy diet, stopping smoking, do not use alcohol to excess, lose some weight, exercise, and if the patient has a high-grade carotid stenosis, consider carotid endarterectomy. Then, obviously, there are some pharmacologic interventions, as shown at the bottom of the slide. We want to get their blood pressure under control, and the new guidelines indicate that blood pressure under control is now defined as 120/80 or even a little less. We want to manage their diabetes. We want to get their lipids, particularly, their LDL down and their HDL up, and we want to consider antiplatelet or anticoagulant therapy, based on the patient’s particular clinical circumstance.
Slide 17: The PROGRESS study shown on the next slide looked at an ACE inhibitor that could or could not have been combined with a diuretic for secondary prevention of stroke for folks who entered into the study with a stroke. What they found overall is that there was a very impressive, about 26%, relative risk reduction for recurrent strokes. You can see here it was successful for a bunch of different end points. Actually, there was a 28% relative risk reduction for total strokes. You can see fatal strokes were reduced by 33%, ischemic strokes by 24%, and, somewhat unexpectedly, cerebral hemorrhages, among the worst type of strokes, were reduced by 50%.
So again this is one of many studies telling us that an ACE inhibitor, perhaps combined with a diuretic, is a very effective antihypertensive regimen for preventing subsequent strokes.
Slide 18: The SPARCL study was recently published, and that looked at high-dose atorvastatin versus placebo in folks with a new TIA or stroke who came into the hospital and could be randomized to treatment within the next few weeks. In SPARCL it was found that there was a 16% relative risk reduction in the time to fatal or nonfatal stroke in favor of folks treated with high-dose atorvastatin versus placebo, and this reduction was statistically significant as shown here, although you really did not start to see the benefit until you treated the patients for about 2 to 2½ years.
Slide 19: What about antiplatelet therapy versus anticoagulation for those patients with a noncardioembolic stroke? Again this is a noncardioembolic stroke. So the types of the patients we are talking about here in the WARSS study were those patients who had small vessel strokes or large artery strokes, but who were not candidates for endarterectomy -- say patients with intracranial disease and the like. And, as you can see from this NIH-sponsored study in terms of percent of patients who had a recurrent ischemic stroke or death, there was really no statistically significant difference between warfarin with a target INR of around 2 versus 1 aspirin a day. So again this is 1 study, but it does show us that warfarin is no better than aspirin for the vast majority of patients with noncardioembolic strokes. So we are not talking about atrial fibrillation or valvular disease with this type of study.
Slide 20: A meta-analysis from the Antithrombotic Trialists Collaboration shown on the next slide, with over 130,000 patients shows that in general, aspirin or antiplatelet agents were very effective with about a 22% risk reduction for the prevention of subsequent vascular events in a wide range of patient populations, including those folks who had a prior ischemic stroke or TIA.
Slide 21: The next slide talks about the efficacy of antiplatelet therapy and prevention of ischemic disease, looking at what they came in with and then subsequent events and then, you can see again, that patients who came in with a prior stroke or TIA, their risk or adjusted percent with subsequent vascular events was reduced by about 17%. For acute MI it was reduced by 27%; prior MI 21%. What this tells us again is that antiplatelet agents are effective for secondary prevention of strokes, but aspirin by itself is really not as effective as perhaps some other agents, since in this study the vast majority of patients were taking aspirin. So a 17% relative risk reduction is okay, but I think we can do better.
Slide 22: So, one of the newer antiplatelet agents that actually has been out now for about 11 years is clopidogrel, and this was studied in the CAPRIE study, which was a prospective, randomized, blinded trial of patients with symptomatic ischemic vascular disease, recent MI, angina, ischemic strokes, symptomatic PAD and the like. What was found in CAPRIE was that there was an almost 9% relative risk reduction in favor of clopidogrel over aspirin for the end point of stroke, MI, and vascular death, with a median follow-up of almost 2 years, and this benefit was statistically significant.
Slide 23: Another study related specifically to stroke patients was the MATCH trial. The MATCH trial had a little different study design because it looked at the combination of aspirin plus clopidogrel, versus clopidogrel by itself. It was an international, randomized, double-blind, prospective trial of over 7500 patients with a recent ischemic stroke or TIA who also had another additional risk factor, such as prior stroke, MI, angina, diabetes, and the like, and in fact a lot of people in the MATCH study did have diabetes. Anyway, these folks were randomized to the combination of aspirin and clopidogrel versus clopidogrel alone, and they were treated for about 18 months.
Slide 24: On the next slide we can see the results of the MATCH study. You can see here that there was about a 1% absolute risk reduction in favor of combination therapy versus clopidogrel alone; however, this was not statistically significant for the primary end point, and, in fact, there was no benefit for the endpoint of any stroke or death. What was worrisome, however, was the increased rate of bleeding complications seen with combination therapy versus clopidogrel alone. You can see for life-threatening bleeds, it was doubled for those patients who took clopidogrel plus aspirin versus clopidogrel alone. And the rate of major bleeding was tripled in those patients taking combination therapy versus clopidogrel alone. I think what MATCH tells us is that clopidogrel monotherapy seems to be about as efficacious as combination therapy, yet it seems to be safer in terms of a reduced rate of bleeding complications.
Slide 25: Speaking of combination therapy, on the next slide we have the layout of the ESPS-2 study. This was a study of aspirin alone, extended-release dipyridamole alone, or aspirin combined with extended-release dipyridamole in patients who had a recent stroke or TIA. It was found here that there was a statistically significant benefit for the reduction of recurrent stroke for those patients who were taking the combination of aspirin and extended-release dipyridamole versus aspirin alone, and this was highly statistically significant. Also, almost anything, aspirin alone, the dipyridamole alone, or the combination alone obviously was better than placebo alone.
Slide 26: The next slide shows us the ESPS-2 results in a little bit different way, which is stroke-free survival. You can see those patients taking the combination of aspirin with extended-release dipyridamole had the highest rate of stroke-free survival with about 92% to 93%. Those patients with placebo had the lowest rate, and in the middle, you can see that those patients taking aspirin alone or dipyridamole alone had sort of middle rates in the high 80%. Again, this is yet another piece of data showing us the efficacy of aspirin combined with extended-release dipyridamole for secondary stroke prevention.
Slide 27: In a post-hoc analysis of the ESPS-2 study cohort, what was interesting is that those people who were particularly at high risk judged by either the Framingham stroke score or the SPI risk, really seem to show enhanced benefit from combination therapy versus aspirin alone. You can see that the event rates were lowered by about 3% between the aspirin alone and the combination group for the high-risk group in the Framingham, and the moderate-risk group for the SPI risk score. I would not make much out of the high-risk group for the SPI score because there were less than 300 patients there, and it was hard to get statistical significance with so few patients. Yet even in that group, you see more than 2% absolute risk reduction in favor of combination therapy.
Slide 28: Now there was another study recently published in Lancet called the ESPRIT study.
This was a study of over 2700 patients from 79 hospitals in 14 countries, mostly Europe. They were enrolled within 6 months of a TIA or a nondisabling stroke. Patients were assigned to take aspirin with various doses, with or without dipyridamole. The vast majority took extended-release dipyridamole, as it is used in the combination form of Aggrenox. The primary end point was the composite of death from all vascular causes, stroke, MI, or major bleeding complications, so a little bit of a different composite end point than we are used to for other studies, so again, stroke, MI, vascular death or major bleeding.
Slide 29: So, in ESPRIT it was found that there was a statistically significant benefit for the primary end point in favor of the group taking aspirin with dipyridamole and, again, mostly extended-release dipyridamole, versus aspirin alone. So this very much mirrors what we are seeing in the ESPS-2 study, which again was published about 10-11 years ago.
Slide 30: A very important ongoing study that many of us are looking forward to with a great deal of enthusiasm is the PRoFESS study. PRoFESS is the largest secondary stroke prevention trial ever done, with over 20,000 patients. It's a prospective, randomized, double-blind, active control phase 4 trial. It is going to compare the antiplatelet regimen of aspirin with extended-release dipyridamole versus clopidogrel by itself for secondary stroke prevention. In addition to the antiplatelet arm, because of a factorial design, there is going to be another arm built into the study where ½ of the patients will get the ARB telmisartan and ½ will not, so that is factorial design. Part of the study will let us know about the efficacy of these different antiplatelet regimens, and the other part will let us know about the efficacy of telmisartan. Inclusion criteria include older patients with ischemic stroke in the past 120 days. The primary end point is the first recurrence of any stroke, so again this is different from the primary endpoint for ESPRIT. The secondary end point will look at the composite of stroke, MI, and vascular death, and other combinations of a secondary end point.
Slide 31: So, where do we stand with the PRoFESS trial? Well, the enrollment for the trial closed last year in July 2006. There were 20,333 patients randomized. At Northwestern, we were one of the sites, and I was the PI at the local site, so I am familiar with the study. The median age was about 66 years. Median time to randomization was 15 days, and about 40% were randomized within 10 days, which is, in fact, very good. If you look at the presumed stroke etiology of randomized patients in PRoFESS, the majority, or 52%, had small vessel lacunar strokes, a little bit more than ¼, 28%, had evidence of large vessel disease. Very few patients had cardioembolic stroke, and about 15% had stroke of unknown etiology. It is amazing but true that even with our high technology and advanced imaging and testing, most studies show that between 15% and 20% or even 25% of stroke patients end up being classified as stroke of unknown etiology, but there will be a fair number of them in the PRoFESS study also.
Slide 32: What about a combined reduction strategy? Well, there have been meta-analyses done that try to quantify the benefits and extrapolate the results from these various randomized controlled trials. There was one study that looked at over 210,000 patients with prior stroke or TIA. They looked at risk reductions such as diet and exercise, using antiplatelet therapies such as aspirin, using statin therapy and treating them aggressively for hypertension. From this analysis it was found that using these 5 strategies could lead to about an 80% relative risk reduction over 5 years for the risk of recurrent stroke. It was thought that additional gains could also be realized by adding more intensive therapies, including dual antiplatelet regimens, intensifying the antihypertensive regimen and perhaps using higher doses of various statin agents. Now, of course, this is a meta-analysis. It is an extrapolation. It is not really a real-world scenario. I think most of us who treat stroke day in and day out would be thrilled but amazed with an 80% risk reduction. That is very hard to achieve because of compliance, side effects, patients getting older and sicker and the like. But I will say that if we can see a relative risk reduction even approaching that, maybe 50% or 60%, that would be tremendous. That would save a lot of people, caregivers, insurance companies and the like of the medical and social and financial burden of having a recurrent stroke.
Slide 33: The next slide talks about the various guidelines. The recent AHA/ASA antithrombotic guidelines for secondary stroke prevention say very clearly that use of an antiplatelet agent rather than anticoagulation is recommended, and that is particularly for patients with a noncardioembolic stroke or TIA. That is the Class I, Level I recommendation. That is as good as it gets. Either of the following is acceptable as initial therapy: aspirin by itself, aspirin combined with extended-release dipyridamole or clopidogrel alone, and you can see that the combination of aspirin and extended-release dipyridamole is recommended over aspirin with the Class IIA, Level A recommendation. Clopidogrel instead of aspirin, that is a Class IIB, Level B recommendation and then obviously if patients are aspirin-allergic they should use clopidogrel. For patients who have an ischemic stroke while taking aspirin, there is no evidence that increasing the dose of aspirin provides any benefit. We are doing work on this, and it is in the area broadly of aspirin resistance to see if that may provide some benefit, but currently it is not recommended because of lack of data.
Slide 34: The next slide talks about how to treat patients with strokes of presumed cardiogenic embolic etiology. Here the recommendation is warfarin with an INR of 2.5, range of 2.0 to 3.0, particularly in those patients with atrial fibrillation or evidence of rheumatic mitral valve disease. For patients with mechanical heart valves, the recommended target INR is 3.0 with a range of 2.5-3.5. For patients unable to take warfarin, the current recommendation is to take aspirin, 325 mg/day. It may not be as potent as warfarin, but there are some data that it does provide some benefit.
What about the addition of aspirin to warfarin therapy? This is thought to be helpful for patients who have recurrent cardioembolic strokes or TIAs, or systemic emboli while on warfarin therapy with a therapeutic INR. However, it is important to remember that the combination does increase the risk of bleeding complications, so we usually recommend using low-dose aspirin.
Slide 35: So, returning to our case on the next slide, in follow-up, Hilda is encouraged to start taking her blood pressure medications and a statin to reduce her lipids. It is also recommended that she begin taking the combination of aspirin and extended-release dipyridamole for secondary stroke prevention. She is also advised very strongly to quit smoking and enroll in a supervised exercise program. Exercise and healthy diet can do a lot, in addition to stopping smoking.
Well, that concludes the presentation. Thank you for your participation.
