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Stroke

Ischemic stroke continues to have a major impact on the public health of our nation. Ranking among the leading causes of death, stroke is far more disabling than fatal and results in enormous costs measured in both health-care dollars and lost productivity. Once considered untreatable, ischemic stroke has become subject to intensive scrutiny in recent years. Considerable research has led to a better delineation of risk factors, as well as an expanded understanding of pathophysiologic subtypes. Innovative acute therapies are being applied in a manner analogous to the

Definitions of TIA and Stroke

Ischemic stroke is characterized by the abrupt or ictal onset of neurologic dysfunction due to inadequate perfusion of the brain. By conventional clinical definitions, if the neurological symptoms continue for more than 24 hours, a person is diagnosed with ischemic stroke. Otherwise, a focal neurological deficit lasting less than 24 hours is defined as a transient ischemic attack (TIA). However, with the advent of more sensitive brain imaging, acute cerebral infarcts have been identified even when symptoms last less than 24 hours. The most recent definition of

Definition of the Infarct Subtype

There are multiple mechanisms which may lead to brain ischemia. Hemodynamic infarction originates when there is an impediment to normal perfusion usually caused by a severe arterial stenosis or occlusion due to atherosclerosis and coexisting thrombosis. Embolism occurs When a particle of thrombus originating from a more proximal source (arterial or cardiac) travels through the vascular system and leads to a distal occlusion. Small vessel disease occurs when lipohyalinosis or local atherosclerotic disease leads to an occlusion of a small penetrating artery. Less frequent conditions which lead to reductions in cerebral perfusion and result in infarction are: arterial dissection, primary or secondary vasculitis, hypercoagulable states, vasospasm, systemic

Atherosclerotic Infarction

Atherosclerotic plaque at a bifurcation or curve in one of the larger vessels leads to progressive stenosis with the final large artery occlusion due to thrombosis of the narrowed lumen. Arteriosclerotic plaques may develop at any point along the carotid artery and the vertebral-basilar system, either extracranial or intracranial. The most common sites are the bifurcation of the common carotid artery into the external and internal carotid arteries, the origins of the middle and anterior cerebral arteries, and the origins of the vertebral from the subclavian arteries. The site of infarction depends on the collateral flow, but is usually in the distal fields or border zones. Specifying the degree of stenosis that will lead to perfusion difficulty is dependent on multiple factors and is often not easily defined. Classification schemes have relied on stenoses greater than 70 to 80% as more predictive of impending hemodynamic compromise.

Cardiac Embolism

The most common sources of cardiac embolism include: atrial fibrillation, valvular heart disease (mitral stenosis, mitral regurgitation, rheumatic heart disease); intracardiac thrombus particularly along the left ventricular wall (mural thrombus) after anterior myocardial infarction or in the left atrial appendage in patients with atrial fibrillation; ventricular or septal aneurysm; and cardiomyopathies leading to stagnation of blood flow and an increased propensity for the formation of intracardiac thrombus.

Embolism is inferred when the brain image demonstrates an infarction confined to the cerebral surface territory of a single branch, combinations of infarcts involving branches of different divisions of major cerebral arteries, or hemorrhagic infarction. The difficult problem in arriving at a diagnosis of embolism is the identification of the occluding particle and the source. Mural thrombi and platelet aggregates are remarkably evanescent, as has been inferred by findings on angiography. Embolic fragments are found in over 75% of cases angiogramed within 48 hours of

Small vessel, Lacunar Infarction

These strokes have distinctive clinical syndromes with a small zone of ischemia confined to the territory of a single vessel. They are understood to reflect arterial disease of the vessels penetrating the brain to supply the internal capsule, basal ganglia, thalamus, corona radiata and paramedian regions of the brainstem. There are disagreements about the pathogenesis of lacunar infarcts with some favoring the use of the term "lacune" to describe size and location without indicating a specific pathology. Only a handful have been pathologically studied by serial section and documented a tiny focus of microatheroma or lipohyalinosis stenosing one of the deep penetrating arteries. The arterial damage is usually the result of long-standing hypertension or

Cryptogenic Infarction

Despite efforts to arrive at a diagnosis, the cause of infarction in a discouragingly large number of cases remains undetermined. Some cases may be unexplained because no appropriate laboratory studies are performed, while others are due to the improper timing of the appropriate laboratory studies. The most frequent circumstances are when normal or ambiguous findings are reached despite appropriate laboratory studies performed at the appropriate time. Results from the Stroke Data Bank indicated that large artery atherosclerotic occlusive disease was a less frequent cause

Identify Stroke Risk Factors

Nonmodifiable stroke risk factors include age, gender, heredity, and ethnicity. There is an exponential increase in incidence of stroke with age, and the majority of strokes occur in persons over 65 years of age. Men have a greater stroke incidence than women, but women often live long enough to experience stroke and, therefore outnumber men in some stroke studies. A history of maternal stroke appears to be another gender-related risk factor. Stroke mortality among African-Americans is double that of white Americans. The incidence of stroke has been found to be greater in African-Americans, but further study is needed to assess the importance of referral and selection biases, confounding risk factors, and differential access to medical care. Little information is available regarding the rapidly growing Hispanic population.

Major reductions in stroke morbidity and mortality are more likely to arise from identification and control of modifiable factors in the stroke-prone individual. Modifiable stroke risk factors include: hypertension, cardiac disease (particularly atrial fibrillation), diabetes, hypercholesterolemia, asymptomatic carotid stenosis, cigarette use, alcohol abuse, and

Risk Factor Modification

Risk factor modification may be attempted either through the "high risk approach" which identifies and seeks to modify the degree of risk in individuals with increased risk of disease; or through a "mass" approach which targets modification of risk factors detectable through the screening of large populations. Gorelick has estimated the potential savings, in lives and dollars, associated with either a "mass" or "high risk" prevention program. Based on the estimated prevalence of risk factors and their attributable risks for stroke in the United States, it is estimated that 246,500 strokes could be prevented from the control of hypertension alone and associated with a savings of $12.33 billion. A prevention program aimed at cigarette smoking could prevent over 61,000 strokes with an associated savings of over $3 billion. Even if these programs were only 25% successful in reducing hypertension and smoking, over $3.8 billion may be saved in stroke related care. Treatment of atrial fibrillation and modification of heavy alcohol use could eliminate 47,000 and 23,500 strokes, respectively.

Hypertension Control

There are very few studies which have documented that treatment of hypertension will decrease the risk of stroke occurrence after TIA or stroke recurrence after minor stroke. Numerous prospective studies and clinical trials, however, have consistently shown a decreased risk of stroke with control of mild, moderate, and severe hypertension in all age groups of stroke-free subjects. A meta-analysis of 9 prospective studies including 420,000 individuals followed for 10 years found that stroke risk increased by 46% for every 7.5mm Hg increase in diastolic blood

Carotid Endarterectomy for Asymptomatic Carotid Stenosis

The efficacy of carotid endartectomy in asymptomatic carotid stenosis has been evaluated in three separate clinical trials: CASANOVA (Carotid Artery Stenosis with Asymptomatic Narrowing: Operation Versus Aspirin), Veterans Administration Asymptomatic Carotid Endartectomy Study, and ACASS (Asymptomatic Carotid Artery Surgery Study). While CASANOVA found no confirmatory data to support carotid endartectomy for treatment of asymptomatic carotid disease, this trial excluded all cases with high grade stenosis greater than 90%. The Veterans Administration trial confirmed a decrease in neurological events, specifically transient ischemic attack (outcomes reduced from 20% to 8%), associated with the carotid endartectomy treatment group versus the medical treatment group, but no significant reduction for ipsilateral stroke.

Patients eligible for ACASS were under age 80 with asymptomatic carotid stenosis greater than 60% and could not have any unstable cardiac disease. Centers were screened for the accuracy of carotid Duplex Doppler in detecting carotid stenosis greater than 60% and the expertise of the operating surgeons with established surgical morbidity and mortality of less than 3%. Overall, the 30-day ipsilateral stroke or death rate among the surgically treated patients was only 2.3%. The trial found a 5-year ipsilateral stroke risk of 10.5% among the medical group and 4.8% in the surgical group. There was a 55% risk reduction of ipsilateral stroke associated with carotid endarectomy. The benefit for men was greater than for women (risk reduction 69% vs. 16%). Further subgroup analyses are pending. Among those patients with asymptomatic carotid stenosis greater than 60% who have an acceptably low risk of operative complications, endarterectomy confers a significant reduction in stroke risk as long as the surgeon can maintain the operative risk below 3%.

Specific Treatments for Patients with Tia or Minor Stroke

Depending on the mechanism of the cerebral ischemic event, there are now options from which to chose for the prevention of first or recurrent stroke. Newer treatments such as thrombolysis and neuroprotection may prove beneficial in the acute setting, while other therapies are aimed at reducing the stroke recurrence risk. One early decision which must be addressed among patients presenting with TIAs or minor strokes is whether to chose surgery versus medical therapies for stroke prevention.

Carotid Endarterectomy

Surgical clinical trials have documented the benefit of carotid endarterectomy to reduce the risk of ischemic stroke in some symptomatic persons. In the North American Symptomatic Carotid Endarterectomy Trial (NASCET) among persons with TIA or minor stroke and an ipsilateral carotid stenosis of 70% or more, the 2-year risk of ipsilateral stroke was 9% in the surgical group and 26% in the medical group (ASA 1300 mg/day). The VA Cooperative Study showed that among those with greater than 50% carotid stenosis, the risks of stroke after a mean follow-up of 11.9 months were 7.7% in the surgical group and 19.4% in the non-surgical group. The European Carotid Surgery Trial (ECST) demonstrated similar findings as in the latter two studies for high-grade symptomatic carotid stenosis, but there was no significant benefit of surgery for those with 0-29% stenosis. Recent NASCET data has extended the benefits of carotid endarterectomy to persons with symptomatic carotid stenosis of greater than 50%. This degree of stenosis is based on the NASCET angiographically-based measurement and is equivalent to approximately 75% stenosis by ECST criteria and greater than 60-80% stenosis by carotid Duplex Doppler criteria.

The consensus is clear that for patients with a TIA or minor stroke and ipsilateral carotid stenosis more than 50-60%, then carotid endarterectomy is the best option for prevention of a recurrent event. For those with <50-60% stenosis, endarterectomy offers little benefit compared to medical therapy.

Antithrombotic Agents

Antithrombotic agents are ultimately aimed at interfering with the process of thrombosis or formation of intravascular clot which involves platelets and fibrin. Antiplatelet agents deter the adherence of platelets to the wall of an injured vessel or to one another. This is an early step in the generation of a thrombus. Anticoagulants prevent the formation and propagation of fibrin which is the essential building block of a thrombus. For cerebral ischemia, a variety of antithrombotic agents have been proven to be of value in the prevention of ischemic stroke after transient ischemic attack, completed infarction, or when certain high-risk conditions are detected such as nonvalvular atrial fibrillation, valvular heart disease, or after acute myocardial infarction. These antithrombotic agents include antiplatelet drugs (aspirin, ticlopidine, dipyridamole, and clopidogrel) and anticoagulants (warfarin). New antiplatelet agents are being tested in a variety of circumstances among patients with cerebrovascular disorders.

Aspirin

Numerous clinical trials have been done comparing aspirin with placebo for the prevention

of stroke and death after TIA or minor stroke. The Antiplatelet Trialist Collaboration Group have used meta analyses to combine the results of these various antiplatelet studies in which ASA was the most widely used agent. In their most recent analyses of 17 trials among persons with a past history of stroke or TIA, they reported an odds reduction of 22% for non-fatal stroke, non-fatal MI or vascular death with a 2-year risk of 18% for those treated with antiplatelets and 22% for controls. Few of the individual aspirin studies were directed at the efficacy of aspirin in preventing recurrent stroke after an established stroke. In the meta-analyses among those with a completed stroke, the odds reduction was 16% for non-fatal stroke, non-fatal MI or vascular death. Individual aspirin studies have sometimes failed to find a beneficial effect for women. However, in the meta-analyses similar reductions were found for women and men, young and old, hypertensives and normotensives and diabetics and non-diabetics.

The issue of the dose of aspirin needed to prevent stroke is still controversial. Recommendations range from a low of 30 mg per day to a high of 1300 mg per day. The data for the efficacy of stroke prevention for lower doses is available only from trials involving patients with TIA and minor stroke. Gastrointestinal hemorrhage and other aspirin-related side effects are clearly reduced with the lower doses. The Antiplatelet Trialist's Collaboration Report cited three trials using doses of 300-325 daily and compared the outcome for major vascular events, including stroke, to the 15 trials using 900-1500 daily. The authors concluded "...the studies of 300-325 mg/day appeared to have yielded results that were at least as good as those yielded by 900-1500 mg/day." However, a review of stroke trials found that the risk reductions were not as great with the low dose aspirin programs compared to the higher dose programs. They stated that this "raised the possibility that 325 mg/day or less of aspirin may not be equally effective as 975 mg/day or more." The data from aspirin trials suggest that a dose of aspirin as low as 325 mg is better tolerated and might prove as effective as the higher doses of 1000-1300 mg. In 1998, the US Food and Drug Administration revised their recommendations to endorse 50-325 mg of ASA per day as the standard dose to prevent stroke in TIA and stroke survivors.

Ticlopidine

The other antiplatelet agent that has proven efficacy in stroke prevention is ticlopidine. In the Canadian American Ticlopidine Study, ticlopidine was compared to placebo after a completed non-cardioembolic stroke among 1053 patients. Ticlopidine resulted in a 23% risk reduction in an intention-to-treat analysis and a 30% reduction in the efficacy analysis. The risk reduction for nonfatal or fatal recurrent stroke was 33%. In the Ticlopidine Aspirin Stroke Study, ticlopidine was compared to aspirin (1300 mg/day) among 3069 patients with TIA or minor stroke. Overall, there was a 12% reduction in stroke or death at 3-years, but a 47% risk reduction in fatal or non-fatal stroke was observed during the first year for those treated with ticlopidine compared to aspirin. Benefits were found both among men and women and the effect was observed in the subgroup with minor stroke.

Dipyridamole

Trials using other antiplatelet agents, such as sulfinpyrazone and suloctidil, have not been as effective as aspirin or have not demonstrated any added benefit to aspirin alone. Dipyridamole was not thought to have any added benefit to aspirin based on the French AICLA trial, however results from the European Stroke Prevention Stroke Study II have indicated that 200 mg BID of modified-release Dipyridamole was more effective than Aspirin (25 mg BID) in the prevention of stroke, myocardial infarction and vascular death after TIA or minor stroke. In this trial 6602 patients were randomized in a factorial design, 76% with stroke and 24% with TIAs. Primary endpoints were stroke, death, and stroke or death together. Patients were followed for 2 years. The relative risk reduction of stroke was 18% for aspirin, 16% for dipyridamole, and 37% for the combination of the two. The relative risk reduction of stroke or death was 13% for aspirin, 15% for dipyridamole, and 24% for the combination of the two. Factorial analysis also demonstrated a highly significant effect of ASA and dipyridamole for preventing TIA. Headache was the most common adverse event and occurred more frequently in the dipyridamole group. Bleeding and GI hemorrhage was more common in patients taking ASA compared to placebo or dipyridamole. The combined long-acting formulation is not yet available or approved in the U.S.

Clopidogrel

Clopidogrel, a thienopyridine derivative similar to ticlopidine, is a new antiplatelet agent which is an inhibitor of platelet aggregation induced by adenosine diphosphate. This agent at a dose of 75 mg BID was recently compared to aspirin (325 mg per day) in reducing the risk of ischemic stroke, myocardial infarction, or vascular death among patients with atherosclerotic vascular disease. Nearly 20,000 patients with stroke, MI, or peripheral vascular disease were recruited over 3 years with a mean follow-up of 1.9 years. Patients treated with clopidogrel had a 5.32% risk of stroke, MI, or vascular death compared to 5.83% with ASA (p=.043). Among the stroke subgroup, there was a nonsignificant reduction from 7.71% to 7.15% in outcome events, however the number of non-fatal strokes were reduced from 322 to 298 with clopidogrel. The most significant effects were observed for the subgroup with PAD. Among patients with PAD or stroke with a prior history of MI, the event rate reduced from 10.74% to 8.35% with clopidogrel (relative risk reduction of 22.7%). The medicine was safe and was not associated with an increased risk of neutropenia. The drug is now FDA approved.

Warfarin

Warfarin is an oral anticoagulant which has been demonstrated to be effective in the prevention of cardioembolic stroke. Recent randomized clinical trials have evaluated the relative merits of warfarin or aspirin in patients with asymptomatic nonvalvular atrial fibrillation. Warfarin is beneficial among patients with prosthetic valves and after acute myocardial infarction to reduce the risk of thromboembolic stroke. Those with mechanical valves are usually treated with long-term oral anticoagulants, while those with bioprosthetic valves may be treated with antiplatelet agents. The combination of low-dose aspirin with warfarin was found to be more effective than warfarin alone in reducing mortality and major systemic embolism among patients with prosthetic valves plus atrial fibrillation or a history of thromboembolism. In the Warfarin Reinfarction Study, warfarin was superior to placebo in reducing the likelihood of recurrent MI,

Acute Stroke Treatments

In the acute setting, thrombolysis with TPA has been approved by the FDA for the treatment of ischemic stroke where the therapy can be instituted within 3 hours of symptoms. The NIH TPA trials demonstrated a consistent and persuasive improvement in 3-month outcome based on the NIH Stroke Severity Scale, Glasgow Outcome Score, Barthel Index of Activities of Daily Living and the Rankin Score (Global Test OR=l.7, p=0.008). The TPA was given at a dose of 0.9 mg per Kg for a maximum of 90 mg with 10% as a bolus and the remainder through a 1-hour IV infusion. There was an elevated risk of intracerebral hemorrhage or hemorrhagic infarction (symptomatic intracranial hemorrhage risk of 6% to 7%). There were numerous exclusion criteria including no evidence of any recent bleeding or chance of bleeding diathesis or uncontrolled hypertension. We must choose our patients accordingly when we consider the use of TPA.

Data from the International Stroke Trial and the Chinese Aspirin Stroke Trial have indicated that the use of aspirin acutely among patients treated within 48 hours will reduce stroke recurrence risks and mortality. The use of heparin is still controversial. Subcutaneous heparin at 12500 BID was found to increase the risk of hemorrhage, while 5000 BID seemed safe and offered some