Susan R. Winkler
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Understand the types of cerebrovascular disease including transient ischemic attack, cerebral infarction, and cerebral hemorrhage.
2. Understand the pathophysiology of cerebral ischemia and cerebral hemorrhage.
3. Identify the modifiable and nonmodifiable risk factors associated with ischemic stroke and hemorrhagic stroke.
4. Identify risk factors for ischemic stroke in a patient and provide the appropriate patient education.
5. Discuss the various treatment options for acute ischemic stroke and hemorrhagic stroke.
6. Determine whether thrombolytic therapy is indicated in a patient with acute ischemic stroke.
7. Develop an appropriate patient-specific therapeutic plan for acute ischemic stroke.
8. Develop an appropriate therapeutic plan for the outpatient management of a patient with ischemic stroke, including an appropriate agent to prevent stroke recurrence.
KEY CONCEPTS
Strokes can either be ischemic (88%) or hemorrhagic (12%).
Ischemic stroke is the abrupt development of a focal neurologic deficit that occurs due to inadequate blood supply to an area of the brain. Most often, this is due to a thrombotic or embolic arterial occlusion leading to cerebral infarction.
Hemorrhagic stroke is a result of bleeding into the brain and other spaces within the CNS and includes subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), and subdural hematomas.
There are two main classifications of cerebral ischemic events: transient ischemic attacks and cerebral infarction.
A major goal in the long-term treatment of ischemic stroke involves the prevention of a recurrent stroke through the reduction and modification of risk factors.
All patients should have a brain CT scan or MRT scan to differentiate an ischemic stroke from a hemorrhagic stroke, as the treatment will differ accordingly and thrombolytic (fibrinolytic) therapy must be avoided until a hemorrhagic stroke is ruled out.
In carefully selected patients, alteplase is effective in limiting the infarct size and protecting brain tissue from ischemia and cell death by restoring blood flow. Treatment should preferably be given within 3 hours and not more than 4.5 hours after symptom onset. Earlier treatment is preferred due to improved outcomes.
Early aspirin (ASA) therapy with an initial dose of 50 to 325 mg is recommended in most patients with acute ischemic stroke within 48 hours after stroke onset.
Selection of the initial antiplatelet agent for secondary prevention of ischemic stroke should be individualized. Clopidogrel and the combination of extended-release dipyridamole and immediate-release ASA are preferred over ASA monotherapy.
There is no proven treatment for ICH. Management is based on neurointensive care treatment and prevention of complications. Oral nimodipine is recommended in SAH to prevent delayed cerebral ischemia.
EPIDEMIOLOGY
Cerebrovascular disease (CVD), or stroke, is the third leading cause of death in the United States and the second most common cause of death worldwide. Approximately 780,000 strokes occur in the United States each year. New strokes account for 600,000 of this total, while recurrent strokes account for the remaining 180,000 strokes each year. Stroke is the leading cause of long-term disability in adults, with 90% of survivors having residual deficits. Moderate to severe disability is seen in 70% of survivors. The American Heart Association estimates that there are over 4.7 million survivors of stroke in the United States. The societal impact and economic burden is great, with costs exceeding $65 billion per year in the United States. Stroke mortality has declined due to improved recognition and treatment of risk factors; however, risk factor management is still inadequate. Stroke incidence increases with age, especially after age 55, resulting in an increased stroke incidence due to aging of the population.1
ETIOLOGY
Strokes can either be ischemic (88% of all strokes) or hemorrhagic (12% of all strokes). Figure 11–1 provides a classification of stroke by mechanism. Ischemic stroke is the abrupt development of a focal neurologic deficit that occurs due to inadequate blood supply to an area of the brain. Most often, this is due to a thrombotic or embolic arterial occlusion leading to cerebral infarction. A thrombotic occlusion occurs when a thrombus forms inside an artery in the brain. An embolism refers to a clot originating either inside or outside of the cerebral vessels in which a piece of the clot breaks loose and is carried either further through or into the cerebral vessels until it lodges causing occlusion. An outside source of emboli is often the heart causing cardioembolic stroke.
Hemorrhagic stroke is a result of bleeding into the brain and other spaces within the CNS and includes subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), and subdural hematomas. SAH results from sudden bleeding into the space between the inner layer and middle layer of the meninges, most often due to trauma or rupture of a cerebral aneurysm or arteriovenous malformation (AVM). ICH is bleeding directly into the brain parenchyma, often as a result of chronic, uncontrolled hypertension. Subdural hematomas result from bleeding under the dura which covers the brain and most often occur as a result of head trauma.
CLASSIFICATION
Cerebral Ischemic Events
There are two main classifications of cerebral ischemic events: transient ischemic attack (TIA) and cerebral infarction. A TIA is a temporary reduction in perfusion to a focal region of the brain causing a short-lived disturbance of function. TIAs have a rapid onset (5 minutes) and short duration (2-15 minutes, up to 24 hours). The symptoms vary depending on the area of the brain affected; however, no deficit remains after the attack. The classic definition of TIA is based on symptom duration of less than 24 hours, while symptoms lasting 24 hours or greater have been categorized as cerebral infarction. Improved brain imaging techniques have revealed that clinical symptoms lasting greater than 1 hour but less than 24 hours are often cerebral infarction. For this reason, it has been proposed that the definition of TIA be changed to include clinical symptoms lasting less than 1 hour with no evidence of cerebral infarction. A TIA maybe the only warning of an impending stroke, with the greatest risk occurring in the first week. Cerebral infarction is similar to a TIA; however, symptoms last longer than 24 hours, and in 90% of patients residual deficits remain after the event.
FIGURE 11–1. Classification of stroke. (From Fagan SC, Hess DC. Stroke. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008: 374, with permission.)
Hemorrhagic Events
A sudden severe headache, nausea and vomiting, and photophobia may be the first signs and symptoms of hemorrhagic stroke. Neck pain and nuchal rigidity may also be experienced at the time of the hemorrhage. Patients may complain that the headache is “the worst headache of my life,” especially if the cause is a SAH. It is important to note that a diagnosis of the type of stroke cannot be made solely on signs and symptoms, as overlap occurs between the types of stroke.
Risk Factors
Assessment of risk factors for ischemic stroke as well as for hemorrhagic stroke is an important component of the diagnosis and treatment of patients. A major goal in the long-term treatment of ischemic stroke involves the prevention of a recurrent stroke through the reduction and modification of risk factors. This is also a major focus of primary prevention (prevention of the first stroke). Risk factors for ischemic stroke can be divided into modifiable and nonmodifiable. Table 11–1 provides a list of risk factors for ischemic stroke. Every patient should have risk factors assessed and treated, if possible, as management of risk factors can decrease the occurrence and/or recurrence of stroke.2
Table 11–1 Nonmodifiable and Modifiable Risk Factors for Ischemic Stroke
|
Nonmodifiable Factors |
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• Age (greater than 55 years of age) |
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• Gender (males greater than females) |
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• Race and ethnicity (African American, Hispanic, or Asian/Pacific Islander) |
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• Heredity |
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• Low birth weight |
|
Modifiable Factors |
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• Hypertension (single most important risk factor) |
|
• Cardiac disease |
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• Atrial fibrillation (most important and treatable cardiac cause of stroke) |
|
• Mitral stenosis |
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• Mitral annular calcification |
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• Left atrial enlargement |
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• Structural abnormalities such as atrial-septal aneurysm |
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• MI |
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• Transient ischemic attacks or prior stroke (major independent risk factor) |
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• Diabetes (independent risk factor) |
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• Dyslipidemia |
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• Lifestyle factors |
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• Cigarette smoking |
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• Excessive alcohol use |
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• Physical inactivity |
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• Obesity |
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• Diet |
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• Cocaine and IV drug use |
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• Low socioeconomic status |
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• Increased hematocrit |
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• Sickle cell disease |
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• Elevated homocysteine level (still under study, but may be related to stroke risk) |
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• Migraine (risk not clear) |
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• Asymptomatic carotid stenosis |
|
• Oral contraceptive use (with estrogen content greater than 50 mcg) |
MI, myocardial infarction.
Nonmodifiable risk factors include age, gender, race/ethnicity, and heredity. Ischemic stroke risk is increased in those greater than 55 years of age, in men, and in African Americans, Hispanics, and Asian Pacific Islanders. It is also increased in those with a family history of stroke. Modifiable risk factors include a number of treatable disease states and lifestyle factors that can greatly influence overall stroke risk. Hypertension is one of the major risk factors for both ischemic and hemorrhagic stroke. For ICH specifically, hypertension has been shown to increase risk by a factor of 3.68.3 Other risk factors for hemorrhagic stroke include trauma, cigarette smoking, cocaine use, heavy alcohol use, and cerebral aneurysm and AVM rupture.
PATHOPHYSIOLOGY
Ischemic Stroke
In ischemic stroke, there is an interruption of the blood supply to an area of the brain either due to thrombus formation or an embolism. Loss of cerebral blood flow results in tissue hypoperfusion, tissue hypoxia, and cell death. Tipid deposits in the vessel wall cause turbulent blood flow and lead to vessel injury, exposing vessel collagen to blood. This vessel injury initiates the platelet aggregation process due to the exposed subendothelium. Platelets release adenosine diphosphate (ADP), which causes platelet aggregation and consolidation of the platelet plug. Thromboxane A2 is released, contributing to platelet aggregation and vasoconstriction. The vessel injury also activates the coagulation cascade, which leads to thrombin production. Thrombin converts fibrinogen to fibrin, leading to clot formation as fibrin molecules, platelets, and blood cells aggregate. Refer to Figures 7–3, 10–3, and 10–4 for a depiction of these processes.
After the initial event, secondary events occur at the cellular level that contribute to cell death. Regardless of the initiating event, the cellular processes that follow may be similar. Excitatory amino acids such as glutamate accumulate within the cells, causing intracellular calcium accumulation. Inflammation occurs and oxygen free radicals are formed resulting in the common pathway of cell death.
There is often a core of ischemia containing unsalvageable brain cells. Surrounding this core is an area termed the ischemic penumbra. In this area cells are still salvageable; however, this is a time-sensitive endeavor. Without restoration of adequate perfusion, cell death continues throughout a larger area of the brain ultimately leading to neurologic deficits. No agents have been shown to be effective at providing neuroprotection at this time.
Hemorrhagic Stroke
The pathophysiology of hemorrhagic stroke is not as well studied as that of ischemic stroke; however, it is more complex than previously thought. Much of the process is related to the presence of blood in the brain tissue and/or surrounding spaces resulting in compression. The hematoma that forms may continue to grow and enlarge after the initial bleed and early growth of the hematoma is associated with a poor outcome. Brain tissue swelling and injury is a result of inflammation caused by thrombin and other blood products. This can lead to increased intracranial pressure (ICP) and herniation.4,5
DESIRED TREATMENT OUTCOMES
The short-term treatment goals for acute ischemic stroke include reducing secondary brain damage by re-establishing and maintaining adequate perfusion to marginally ischemic areas of the brain and to protect these areas from the effects of ischemia (i.e., neuroprotection). The long-term treatment goals include prevention of a recurrent stroke through reduction and modification of risk factors and by use of appropriate treatments.
Patient Encounter, Part 1
GR is a 68-year-old, 64 kg African American male who presents to the emergency department with dizziness and loss of speech that began 1 hour ago. His past medical history is significant for hypertension, diabetes mellitus, dyslipidemia, and benign prostatic hypertrophy (BPH). Social history is significant for smoking one pack per day for the last 38 years. Current medications include metoprolol 50 mg twice daily, insulin NPH 20 units twice daily, and simvastatin 20 mg daily.
What signs and symptoms does GR have that are suggestive of stroke?
What nonmodifiable and modifiable risk factors does GR have for acute ischemic stroke?
Clinical Presentation and Diagnosis of Stroke
General
• The patient may not be able to reliably report the history owing to cognitive or language deficits. A reliable history may have to come from a family member or another witness.
Symptoms
• The patient may complain of weakness on one side of the body, inability to speak, loss of vision, vertigo, or falling. Stroke patients may complain of headache; however, with hemorrhagic stroke, the headache can be severe.
Signs
• Patients usually have multiple signs of neurologic dysfunction, and the specific deficits are determined by the area of the brain involved.
• Hemiparesis or monoparesis occur commonly, as does a hemisensory deficit.
• Patients with vertigo and double vision are likely to have posterior circulation involvement.
• Aphasia is seen commonly in patients with anterior circulation strokes.
• Patients may also suffer from dysarthria, visual field defects, and altered levels of consciousness.
Laboratory Tests
• There are no specific laboratory tests for stroke.
• Tests for hypercoagulable states, such as protein C deficiency and antiphospholipid antibody, should be done only when the cause of stroke cannot be determined based on the presence of well-known risk factors for stroke.
Other Diagnostic Tests
• A CTscan of the head will reveal an area of hyperintensity (white) identifying that a hemorrhage has occurred. The CTscan will either be normal or hypointense (dark) in an area where an infarction has occurred. It may take 24 hours (and rarely longer) to reveal the area of infarction on a CTscan.
• MRI of the head will reveal areas of ischemia earlier and with better resolution than a CTscan. Diffusion-weighted imaging can reveal an evolving infarct within minutes.
• Carotid Doppler studies will determine whether the patient has a high degree of stenosis in the carotid arteries supplying blood to the brain (extracranial disease).
• The ECG will determine whether the patient has atrial fibrillation, which is a major risk factor for stroke.
• A transthoracic echocardiogram will identify whether there are heart valve abnormalities or problems with wall motion resulting in emboli to the brain.
Short-term treatment goals for hemorrhagic stroke include rapid neurointensive care treatment to maintain adequate oxygenation, breathing, and circulation. Management of increased ICP and blood pressure (BP) are important in the acute setting. Long-term management includes prevention of complications and prevention of a recurrent bleed and delayed cerebral ischemia.
Prevention of long-term disability and death related to the stroke are important regardless of stroke type.
GENERAL APPROACH TO TREATMENT
All patients should have a brain CT scan or MRI scan to differentiate an ischemic stroke from a hemorrhagic stroke, as the treatment will differ accordingly and thrombolytic (fibrinolytic) therapy must be avoided until a hemorrhagic stroke is ruled out. A CT scan is the most important diagnostic test in patients with acute stroke. For those with an ischemic stroke, an evaluation should be done to determine the appropriateness of reperfusion therapy. In hemorrhagic stroke, a surgical evaluation should be completed to assess the need for surgical clipping of an aneurysm or other procedure to control the bleed and prevent rebleeding and other complications. Figure 11–2 provides an algorithm for the initial management of the acute stroke patient.
TREATMENT OF ACUTE ISCHEMIC STROKE
Acute ischemic stroke is a medical emergency. Identification of the time and manner of stroke onset is an important determinant in treatment. The time the patient was last without symptoms is used as the time of stroke onset. Because patients typically do not experience pain, determining the onset time can be difficult. It is also important to document risk factors and the previous functional status of the patient to assess current disability due to stroke.
FIGURE 11–2. Acute stroke treatment algorithm. (BP, blood pressure; CEA, carotid endarterectomy; DVT, deep vein thrombosis; IA, intra-arterial; ICA, internal carotid artery; ICH, intracerebral hemorrhage; NINDS, National Institute of Neurological Disorders and Stroke; NS, normal saline; SAH, subarachnoid hemorrhage; t-PA, tissue plasminogen activator.)
Supportive Measures
Acute complications of ischemic stroke include cerebral edema, increased ICP, seizures, and hemorrhagic conversion. In the acute setting, supportive interventions and treatments to prevent acute complications should be initiated.
Tissue oxygenation should be maintained acutely. Measure the oxygen saturation using pulse oximetry and supplement the patient with oxygen if necessary. The oxygen saturation should be maintained at 92% or greater.6 Volume status and electrolytes should be corrected. If required, the blood glucose should be corrected, as both hyperglycemia and hypoglycemia may worsen brain ischemia. When hypoglycemia is present, bolus with 50% dextrose immediately. A blood glucose that is severely elevated should be lowered to less than 200 mg/dL (11.1 mmol/L) using subcutaneous insulin. Recent guidelines suggest that treatment of hyperglycemia poststroke should be more aggressive than previously recommended.7 If the patient is febrile, treat with acetaminophen, as fever is associated with brain ischemia and increased morbidity and mortality after stroke. Alternately, cooling devices can be used.7,8Low-dose unfractionated heparin (UFH) or low-dose low-molecular-weight heparins (LMWHs) administered subcutaneously will significantly decrease the risk of developing venous thromboembolism (VTE) poststroke. UFH 5,000 units subcutaneously every 8 to 12 hours or low-dose LMWHs should be given for VTE prophylaxis in patients who are not candidates for IV alteplase. In patients receiving IV alteplase, the administration of subcutaneous UFH or LMWHs should be delayed 24 hours to avoid bleeding complications.
In the setting of acute ischemic stroke, many patients will have an elevated BP in the first 24 to 48 hours.9 BP should be optimized; however, hypertension should generally not be treated initially in acute ischemic stroke patients, as this may cause decreased blood flow in ischemic areas, potentially increasing the infarction size. The cautious use of antihypertensive medications may be necessary in patients who are otherwise candidates for thrombolytic therapy, including those with severely elevated BP (systolic BP greater than 220 mm Hg or diastolic BP greater than 120 mm Hg), and those with other medical disorders requiring immediate lowering of BP. Tables 11-2 and 11-3provide recommendations on BP management in those eligible and not eligible for alteplase. In those not eligible for alteplase, when BP is lowered, aim for a 10% to 15% reduction. Avoid using sublingual calcium channel blockers, as these may lower BP too rapidly. BP should be checked three times with each reading taken 5 minutes apart.
Table 11–2 BP Recommendations for Ischemic Stroke (Not Eligible for Alteplase)
Table 11–3 BP Recommendations for Ischemic Stroke (Eligible for Alteplase)
Nonpharmacologic Therapy
Carotid Endarterectomy and Other Surgical Procedures
It is unknown whether carotid endarterectomy is of value when performed emergently after stroke, meaning within the first 24 hours after symptom onset.7 Improvement after surgery has been shown in some patients with mild to moderate neurologic deficits. In patients with more severe neurologic deficits, the utility of carotid endarterectomy is unclear. Emergency bypass procedures and middle cerebral artery embolectomy are controversial. Due to the lack of proven efficacy of these procedures when performed emergently in acute ischemic stroke, they are not routinely recommended.
Thrombolytic Therapy
Alteplase
Alteplase (rt-PA; Activase) is an IV thrombolytic (fibrinolytic) that was approved for acute stroke treatment in 1996 based on the results of the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Trial.10The American Stroke Association guidelines include alteplase as the only FDA-approved acute treatment for ischemic stroke and strongly encourage early diagnosis and treatment of appropriate patients.7
Based on several assessment scales, patients treated with alteplase were 30% more likely to have minimal or no disability at 3 months compared with patients given placebo. Alteplase treatment resulted in an 11% to 13% absolute increase in patients with excellent outcomes at 3 months independent of patient age, stroke subtype, stroke severity, or prior use of ASA.11 ICH within 36 hours after stroke onset occurred in 6.4% of those given alteplase versus 0.6% in those given placebo. There was no significant difference in mortality between the two groups at 3 months or 1 year. In carefully selected patients, alteplase is effective in limiting the infarct size and protecting brain tissue from ischemia and cell death by restoring blood flow. Treatment should preferably be given within 3 hours and not more than 4.5 hours after symptom onset. Earlier treatment is preferred due to improved outcomes. A dose of 0.9 mg/kg (maximum 90 mg) is recommended; the first 10% is given as an IV bolus and the remainder is infused over 1 hour. Table 11–4 details the inclusion and exclusion criteria for the administration of alteplase in acute ischemic stroke.
Table 11–4 Inclusion and Exclusion Criteria for Alteplase Use in Acute Ischemic Stroke
|
Inclusion Criteria |
|
• 18 years of age or older |
|
• Clinical diagnosis of ischemic stroke causing a measurable neurologic deficit |
|
• Time of symptom onset well established to be less than 180 minutes before treatment would begin |
|
Exclusion Criteria |
|
• Evidence of intracranial hemorrhage on CT scan of the brain prior to treatment |
|
• Only minor or rapidly improving stroke symptoms |
|
• Clinical presentation suggestive of SAH even with a normal head CT |
|
• Active internal bleeding |
|
• Known bleeding diathesis, including but not limited to (a) platelet count less than 100 × 103/mm3 (100 × 109/L); (b) heparin within 48 hours with an elevated aPTT; or (c) current oral anticoagulant use (e.g., warfarin) or recent use with an elevated PT (greater than 15 seconds) or INR (greater than 1.7) |
|
• Intracranial surgery, serious head trauma, or previous stroke within 3 months |
|
• Suspected aortic dissection associated with stroke |
|
• Suspected subacute bacterial endocarditis or vasculitis |
|
• History of Gl or urinary tract hemorrhage within 21 days |
|
• Major surgery or serious trauma within 14 days |
|
• Recent arterial puncture at a noncompressibie site |
|
• Lumbar puncture within 7 days |
|
• History of intracranial hemorrhage |
|
• Known AVM or aneurysm |
|
• Witnessed seizure at the same time as the onset of stroke symptoms occurred |
|
• Recent acute MI |
|
• SBP greater than 185 mm Hg or DBP greater than 110 mm Hg at the time of treatment, or patient requires aggressive treatment to reduce BP to within these limits |
aPTT, activated partial thromboplastin time; AVM, arteriovenous malformation; DBP, diastolic blood pressure; INR, International Normalized Ratio; Ml, myocardial infarction; PT, prothrombin time; SBP, systolic blood pressure.
Studies following the NINDS trial protocol have supported alteplase use in acute ischemic stroke and have shown similar rates for both response and ICH occurrence. When the clinical trials are pooled, study results show that the sooner alteplase is given after the onset of stroke symptoms, the greater the benefit seen in neurologic outcome.12 Current guidelines recommend alteplase use within 3 hours after stroke onset in appropriate patients and further recommend that alteplase be started as soon as possible within this window of time.11 Based upon a pooled analysis of the clinical trials and the ECASS III trial results, alteplase may provide some benefit if administered within 4.5 hours of symptom onset.11,13
Antiplatelet agents, anticoagulants, and invasive procedures such as insertion of a central line or placement of a nasogastric tube should be avoided for 24 hours after the infusion of alteplase to prevent bleeding complications. Bladder catheterization should be avoided for 30 minutes postinfusion.
Efficacy is measured by the elimination of existing neurologic deficits and the long-term improvement in neurologic status and functioning based on neurologic examinations and other outcome measures. Neurologic examinations should be completed every 15 minutes during the infusion of alteplase, every 30 minutes for the first 6 hours after the infusion, and then every 4 hours up to 24 hours after alteplase administration. In the NINDS trial, neurologic function was assessed 24 hours after the administration of alteplase using the National Institutes of Health Stroke Scale (NIHSS). This scale quantifies neurologic deficits in patients who have had a stroke and is easily performed. At 3 months, the NIHSS and other neurologic assessments were completed.
The major adverse effects of thrombolytic therapy are bleeding, including ICH and serious systemic bleeding. Mental status changes and a severe headache may indicate ICH. Signs of bleeding include easy bruising, hematemesis, guaiac-positive stools, black, tarry stools, hematoma formation, hematuria, bleeding gums, and nosebleeds. Angioedema is a potential side effect that may cause airway obstruction.
Streptokinase
Streptokinase and other thrombolytics, except alteplase, are not indicated for use in acute ischemic stroke. Three large randomized controlled trials evaluating streptokinase were stopped early due to a high incidence of hemorrhage in the streptokinase-treated patients.14–16 Other thrombolytic agents, including tenecteplase, reteplase, desmoteplase, and urokinase, are not recommended for treatment unless associated with a clinical trial.7,17
Intra-arterial Thrombolytics
Intra-arterial (IA) thrombolytics may improve outcomes in selected patients with acute ischemic stroke due to large-vessel occlusion. Patients in two clinical trials received prourokinase (r-pro UK) plus heparin or heparin alone within 6 hours of symptom onset.18,19 Results from the first trial were not statistically significant, but favored r-pro UK, while the results of the second trial showed a statistically significant benefit to r-pro UK. No difference in mortality was found, although the incidence of intracranial hemorrhage was greater in the r-pro UK plus heparin group versus heparin alone. Note in particular, r-pro UK is not FDA approved and is not available for clinical use. Interest in IA thrombolysis has continued as an option for patients who have contraindications to IV alteplase. It may be used in patients with middle cerebral artery occlusion within 6 hours of symptom onset. IA thrombolysis should be performed by qualified personnel and should not delay treatment with IV alteplase in eligible patients.7
Heparin
Full dose IV UFH has been commonly used in acute stroke therapy; however, no adequately designed trials have been conducted to establish its efficacy and safety. Current acute ischemic stroke treatment guidelines do not recommend routine, urgent, full dose anticoagulation with UFH or LMWHs due to the lack of a proven benefit in improving neurologic function and the risk of intracranial bleeding.7,11,20Full dose UFH may prevent early recurrent stroke in patients with large-vessel atherothrombosis or those thought to be at high-risk of recurrent stroke (i.e., cardioembolic stroke); however, more study is required.
The major complications of heparin include evolution of the ischemic stroke into a hemorrhagic stroke, bleeding, and thrombocytopenia. The occurrence of severe headache and mental status changes may indicate ICH. Signs of bleeding mirror those listed for alteplase therapy. The hemoglobin, hematocrit, and platelet count should be obtained at least every 3 days to detect bleeding and thrombocytopenia.
LMWHs and Heparinoids
TFull dose LMWHs and heparinoids are not recommended in the treatment of acute ischemic stroke.7,11,21 Studies with these agents have generally been negative and no convincing evidence exists that these agents improve outcomes after ischemic stroke. An increased risk of bleeding complications and hemorrhagic transformation have been observed.
Aspirin
ASA in acute ischemic stroke has been studied in two large, randomized trials, the International Stroke Trial and the Chinese Acute Stroke Trial.22,23 Patients who received ASA within 24 to 48 hours of the onset of acute stroke symptoms were less likely to suffer early recurrent stroke, death, and disability. Early ASA therapy with an initial dose of 150 to 325 mg is recommended in most patients with acute ischemic stroke within 48 hours after stroke onset. The ASA dose may then be reduced to 50 to 100 mg daily to reduce bleeding complications.11
The administration of anticoagulants and antiplatelet agents should be delayed for 24 hours in those patients receiving alteplase. Clopidogrel either alone or in combination with ASA is not recommended in acute ischemic stroke. Glycoprotein IIb/IIIa receptor inhibitors are not recommended except in the setting of research.7
Ancrod
Ancrod is an investigational agent that acts to decrease plasma fibrinogen levels. It may be beneficial in patients with acute ischemic stroke when administered within 3 hours of symptom onset. Based upon available clinical trials, ancrod appears to have a potential benefit; however, studies are ongoing. It is not recommended for clinical use because efficacy and safety have not been definitively established.7,24
PREVENTION OF ACUTE ISCHEMIC STROKE
Primary Prevention
Aspirin
The use of ASA in patients with no history of stroke or ischemic heart disease reduced the incidence of nonfatal myocardial infarction (MI) but not of stroke. A meta-analysis of eight trials found that the risk of stroke, especially hemorrhagic stroke, was slightly increased with ASA use. Major bleeding risk was also increased with ASA use.25 The Women’s Health Study evaluated over 38,000 women and found a benefit with ASA use in high-risk women 65 years and older.26 A recent meta-analysis found a higher risk of hemorrhagic stroke in men and a greater risk of major bleeding in both men and women.27 Primary prevention guidelines recommend ASA use in older women who are at high-risk for stroke; however, the benefit must be weighed against the risk of major bleeding. No benefit and potentially more risk of hemorrhagic stroke has been found in men, therefore, ASA is not recommended in this group.28
Statin Therapy
Dyslipidemia has not previously been identified as an independent risk factor for stroke; however, recent studies have found a relationship between total cholesterol levels and stroke rate.28 Statin use may reduce the incidence of a first stroke in high-risk patients (e.g., hypertension, coronary heart disease, or diabetes) including patients with normal lipid levels. Stroke risk was decreased by 27% to 32% overall in large clinical trials.29,30 Patients with a history of MI, coronary artery disease (CAD), elevated lipid levels, diabetes, and other risk factors benefit from treatment with a lipid-lowering agent including patients with normal lipid levels.
BP Management
Lowering BP in patients who are hypertensive has been shown to reduce the relative risk of stroke, both ischemic and hemorrhagic, by 35% to 44%.31 All patients should have their BP monitored and controlled appropriately based on current guidelines for BP management.32 Reduction in BP is the main goal as one agent has not been clearly shown to be more beneficial than any other for the primary prevention of stroke.
Smoking Cessation
The relationship between smoking and both ischemic and hemorrhagic stroke is clear. Patients should be assisted and encouraged in smoking cessation as the stroke risk after cessation has been shown to decline over time. Effective treatment options are available including counseling, nicotine replacement products, and oral agents.
Other Treatments
A number of other disease states and lifestyle factors should be addressed as primary prevention of stroke. Atrial fibrillation is an important and well documented risk for stroke. See Chapter 9 for information on stroke prevention in atrial fibrillation. Diabetes, carotid stenosis, cardiac disease, obesity, and physical inactivity are other risks that should be assessed and managed appropriately.
Secondary Prevention
Nonpharmacologic Therapy
Carotid Endarterectomy
The benefit of carotid endarterectomy for prevention of recurrent stroke has been studied previously in major trials.33,34 A recent meta-analysis has been completed that has combined these clinical trials to evaluate 6,092 patients.35Carotid endarterectomy has been shown to be beneficial for preventing ipsilateral stroke in patients with symptomatic carotid artery stenosis of 70% or greater and is recommended in these patients. In patients with symptomatic stenosis of 50% to 69%, a moderate reduction in risk is seen in clinical trials. In those patients with stenosis of 50% to 69% and a recent stroke, carotid endarterectomy is appropriate. In other patients, surgical risk factors and surgeon skill should be considered prior to surgery. Carotid endarterectomy is not beneficial for symptomatic carotid stenosis less than 50% and should not be considered in these patients.
Patient Encounter, Part 2
In the emergency department an IV line is placed, a physical and neurologic exam is completed, and GR is moved to the stroke unit. The CT scan is negative for hemorrhagic stroke.
Identify your treatment goals for GR.
What acute management would be appropriate for GR at this time?
Patients with asymptomatic carotid artery stenosis of 60% or more may benefit from carotid endarterectomy if it is performed by a qualified surgeon with low complication rates (less than 3%). There is considerable controversy over how this information can be applied to clinical practice. Currently, recommendations suggest considering carotid endarterectomy in patients with carotid artery stenosis of 60% to 99% who are between 40 and 75 years of age if there is a 5-year life expectancy and the operative risks are low.36
Carotid Angioplasty
Carotid angioplasty with or without stenting is typically restricted to patients who are refractory to medical therapy and are not surgical candidates. Clinical trials are currently ongoing to further define the role of carotid angioplasty in both symptomatic and asymptomatic patients.
Pharmacologic Therapy
Aspirin
In a recent meta-analysis including 144,051 patients with previous MI, acute MI, previous TIA or stroke, and acute stroke, as well as others at high risk, ASA was found to decrease the risk of recurrent stroke by approximately 25%.37 ASA is an option for initial therapy for secondary prevention of ischemic stroke and decreases the risk of subsequent stroke by approximately 22% in both men and women with previous TIA or stroke.37 A wide range of doses have been used (30 to 1,500 mg/day); however, the FDA has approved doses of 50 to 325 mg for secondary ischemic stroke prevention. Current guidelines recommend varying ASA doses including ASA 50 to 100 mg daily and 50 to 325 mg daily.2,11 Lower ASA doses are currently recommended to prevent the bleeding complications associated with higher doses of ASA. Adverse effects of ASA include GI intolerance, GI bleeding, and hypersensitivity reactions.
Warfarin
Recent clinical trials have not found oral anticoagulation in those patients without atrial fibrillation or carotid stenosis to be better than antiplatelet therapy. In patients without atrial fibrillation, antiplatelet therapy is recommended over warfarin. Patients with atrial fibrillation and a previous TIA or stroke have the highest risk of recurrent stroke. Long-term anticoagulation with warfarin is recommended and is effective in both the primary and secondary prevention of stroke.2,11 The goal International Normalized Ratio (INR) for this indication is 2 to 3.
Ticlopidine
Ticlopidine is slightly more beneficial in stroke prevention than ASA in men and women.38,39 The usual recommended dosage is 250 mg orally twice daily. Ticlopidine is costly, and side effects include bone marrow suppression, rash, diarrhea, and an increased cholesterol level. Neutropenia is seen in approximately 2% of patients. Thrombotic thrombocytopenic purpura (TTP) occurs in 1 of every 2,000 to 4,000 patients treated with ticlopidine. Monitoring of the complete blood count (CBC) is required every 2 weeks for the first 3 months of therapy. Due to the costly laboratory monitoring required and the adverse effect profile, ticlopidine is typically avoided clinically.
Clopidogrel
Clopidogrel is slightly more effective than ASA with a relative-risk reduction of 7.3% more than that provided by ASA.40 The usual dose is 75 mg orally taken once daily. Clopidogrel has a lower incidence of diarrhea and neutropenia than ticlopidine, and laboratory monitoring is not required. There have been eleven case reports of TTP occurring secondary to clopidogrel, with the majority occurring within the first 2 weeks of therapy, therefore, clinicians need to be aware of the potential for the development of TTP with clopidogrel. Clopidogrel should be used as monotherapy for stroke prevention. It is an option for initial therapy and is considered first-line therapy in patients with peripheral arterial disease.
Extended-Release Dipyridamole Plus Immediate-Release Aspirin
Combination therapy with extended-release (ER) dipyridamole plus immediate-release (IR) ASA was more effective than either treatment alone in the European Stroke Prevention Study 2.41 In this study, patients received either placebo, ASA 25 mg twice daily, ER dipyridamole 200 mg twice daily, or a combination of both agents. The individual agents produced risk reductions of 18.1% with ASA and 16.3% with ER dipyridamole, whereas the combination produced a 37% risk reduction. Headache and diarrhea were common adverse effects of dipyridamole, while bleeding was more common in the treatment groups receiving ASA. This is the first study showing that combination antiplatelet therapy has additive effects over each agent alone. The currently available formulation is a combination product containing 25 mg ASA and 200 mg ER dipyridamole. This combination is an option for initial therapy, but is not appropriate for patients who are intolerant to ASA.
Current Clinical Trials
Recent trials have been completed to evaluate other combinations of antiplatelet agents and to compare them against one another. In the MATCH trial, low-dose ASA plus clopidogrel combination therapy did not show a significant benefit compared to clopidogrel alone.42 This trial found that the addition of ASA to clopidogrel increased the risk of major bleeding. The combination of ASA and clopidogrel is not recommended due to these concerns. The ESPRIT trial compared the combination of ASA and dipyridamole to ASA alone.43 ASA was dosed between 30 and 325 mg daily and dipyridamole was dosed at 200 mg twice daily with 83% of patients using ER dipyridamole. This trial showed that the combination of ASA and dipyridamole was more effective at preventing recurrent stroke than ASA alone. Another trial by the PRoFESS Study Group compared the combination of ASA and ER dipyridamole to clopidogrel. Neither agent was shown to be superior.44
Antiplatelet Therapy
The current stroke treatment guidelines from the American College of Chest Physicians recommend ASA, clopidogrel, or combination therapy with ER dipyridamole plus IR ASA as initial antiplatelet therapy for the secondary prevention of stroke.2,11 Selection of the initial antiplatelet agent for the secondary prevention of ischemic stroke should be individualized. Clopidogrel and the combination of ER dipyridamole and IR ASA are preferred over ASA mono-therapy. Therapy is individualized based on patient factors and cost.
Therapeutic failure in this patient population is challenging as no data are available to guide a treatment decision. When a patient is on therapeutic doses of ASA, yet experiences a recurrent TIA or stroke, switching to either clopidogrel or the combination of ASA and ER dipyridamole is a reasonable option. If failure occurs on either clopidogrel or the combination of ASA and ER dipyridamole, switching to the alternate drug maybe appropriate.
BP Management
Hypertension is an important risk factor for stroke; however, it had been unclear if lowering BP reduced the incidence of secondary ischemic stroke. In the PROGRESS trial, it was shown that BP reduction using the angiotensin-converting enzyme inhibitor (ACE-I) perindopril alone resulted in a 28% reduction in recurrent stroke compared to placebo. With the addition of the diuretic indapamide to perindopril, a 43% reduction in stroke recurrence was seen.45 This reduction in stroke incidence occurred even in patients who were not hypertensive. In patients with a previous history of TIA or stroke, the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends a diuretic and an ACE-I.32 Table 11–5 provides drug and dosing recommendations for the treatment of ischemic stroke.
TREATMENT OF ACUTE HEMORRHAGIC STROKE
Supportive Measures
Acute hemorrhagic stroke is considered to be an acute medical emergency. Initially, patients experiencing a hemorrhagic stroke should be transported to a neurointensive care unit. There is no proven treatment for ICH. Management is based on neurointensive care treatment and prevention of complications. Treatment should be provided to manage the needs of the critically ill patient including management of increased ICP, seizures, infections, and prevention of rebleeding and delayed cerebral ischemia. In those with severely depressed consciousness, rapid endotracheal intubation and mechanical ventilation may be necessary. BP is often elevated after hemorrhagic stroke and appropriate management is important to prevent rebleeding and expansion of the hematoma.46 BP can be controlled with IV boluses of labetalol 10 to 80 mg every 10 minutes up to a maximum of 300 mg or with IV infusions of labetalol (0.5-2 mg/min) or nicardipine (5-15 mg/h). Deep vein thrombosis prophylaxis with intermittent compression stockings should be implemented early after admission. In those patients with SAH, once the aneurysm has been treated, heparin maybe instituted.4,5
Patient Encounter, Part 3
GR is ready for discharge after spending 5 days in the hospital.
What would be an appropriate discharge plan for GRat this time?
What specific medications would you recommend upon discharge?
Table 11–5 Recommendations for Pharmacotherapy of Ischemic Stroke
Nonpharmacologic Therapy
Patients with hemorrhagic stroke are evaluated for surgical treatment of SAH and ICH. In SAH, either clipping of the aneurysm or coil embolization is recommended within 72 hours after the initial event to prevent rebleeding. Coil embolization, also called coiling, is a minimally invasive procedure in which a platinum coil is threaded into the aneurysm. The flexible coil fills up the space to block blood flow into the aneurysm thereby preventing rebleeding. Surgical removal of the blood in patients with ICH is controversial, as one large randomized trial did not show a benefit to removal compared with those treated conservatively according to the current guidelines.46,47
Pharmacologic Therapy
Calcium Antagonists
Oral nimodipine is recommended in SAH to prevent delayed cerebral ischemia. Delayed cerebral ischemia occurs 4 to 14 days after the initial aneurysm rupture and is a common cause of neurologic deficits and death. A meta-analysis of 12 studies was conducted and concluded that oral nimodipine 60 mg every 4 hours for 21 days following aneurysmal SAH reduced the risk of a poor outcome and delayed cerebral ischemia.48
Hemostatic Therapy
Recombinant factor VIIa has been shown to have a benefit in the treatment of ICH. The Recombinant Activated Factor VII Intracerebral Hemorrhage Trial compared three different doses and placebo. Doses were 40, 80, or 160 mcg/kg or placebo given as an IV infusion over 1 to 2 minutes within 4 hours after the onset of symptoms. Hematoma growth was decreased at 24 hours, mortality was decreased at 90 days, and overall functioning was increased at 90 days.49 A recent phase III trial showed that recombinant factor VIIa decreased growth of the hematoma, but did not improve survival or functional outcome.50Current treatment guidelines suggest that recombinant factor VIIa infused within the first 3 to 4 hours after onset may be beneficial; however, further study is required before this treatment can be recommended outside of a clinical trial.46
OUTCOME EVALUATION
• Stroke outcomes are measured based on the neurologic status and functioning of the patient after the acute event. The NIHSS is a measure of daily functioning and is used to assess patient status following a stroke.
• Early rehabilitation can reduce functional impairment after a stroke. Recent stroke rehabilitation guidelines have been endorsed by the American Heart Association and the American Stroke Association. These guidelines recommend that patients receive care in a multidisciplinary setting or stroke unit, receive early assessment using the NIHSS, and recommend that rehabilitation is started as soon as possible after the stroke. Other recommendations include screening for dysphagia and aggressive secondary stroke prevention treatments.51
Table 11–6 Monitoring the Stroke Patient
• Table 11–6 provides monitoring guidelines for the acute stroke patient.
Patient Care and Monitoring
1. Assess the patient’s signs and symptoms including the time of symptom onset and the time of arrival in the emergency department.
2. Perform thorough neurologic and physical examinations evaluating for potential causes of the stroke.
3. Perform a CTscan to rule out a hemorrhagic stroke prior to administering any treatment.
4. Evaluate the inclusion and exclusion criteria for thrombolytic therapy to determine appropriateness for the patient.
5. Transfer the patient to a stroke center if available and develop a plan for the acute management of the patient.
6. Determine the patient’s risk factors for stroke.
7. Develop a plan for the long-term management of risk factors in order to prevent a recurrent stroke.
8. Educate the patient on appropriate lifestyle modifications that will reduce stroke risk.
9. Educate the patient on their medication regimen stressing the importance of adherence.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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