Asma M. Moheet
Definition and Etiology
A stroke is defined as an acute loss of neurological function due to an abnormal perfusion of brain tissue. Most strokes are ischemic (87%) in nature and commonly result from an arterial obstruction by a thrombus or embolus. Hemorrhagic strokes (13%) are caused by rupture or leak of a blood vessel either within the primary brain tissue or subarachnoid space. This chapter provides a clinical approach to the evaluation and management of stroke, with a focus on ischemic stroke.
Prevalence and Risk Factors
Because stroke is the leading cause of morbidity and the fourth-leading cause of death in the United States today, optimal reduction of risk factors is paramount in preventing and managing stroke. Modifiable and nonmodifiable stroke risk factors are listed in Table 1. In 2005, the prevalence of stroke in noninstitutionalized adults was 5.8 million in the United States alone. Based on American Stroke Association data, the estimated direct and indirect cost of stroke for 2008 was $65.5 billion, with an estimated lifetime cost of $140,000 per patient.
Table 1: Cerebrovascular Disease Risk Factors
Pathophysiology and Natural History
The mechanism of stroke is an important characteristic of ischemic strokes and help predict outcomes after stroke and assess risk of stroke recurrence. Based on prior clinical trials, a subclassification scheme of five etioloiges of ischemic stroke has become widely accepted. They are large-artery atherosclerosis, embolism, small-vessel disease, stroke of other determined etiology, and stroke of undetermined etiology.
High-grade stenosis or occlusion of the major intra- and extra-cranial arteries, which include the internal carotid artery, the vertebral artery, the basilar artery, and other major branches of the circle of Willis, occur due to deposition of plaque and may lead to a flow-dependent state of perfusion. With interruption of flow due to acute plaque rupture or a prolonged low-flow state due to relative hypotension, a loss of adequate cerebral perfusion results in ischemia and focal neurologic deficit. A more common cause of stroke in the setting of large-artery atherosclerosis is the formation of thrombus that can block flow directly or dislodge to form an atheroembolism that obstructs a distal vessel.
Turbulent or stagnant flow states in the heart can result in formation of thrombi. These thrombi can dislodge and occlude blood vessels in the intracranial circulation farther downstream. The most common cause of cardioembolic stroke is atrial fibrillation. Other causes include severe left ventricular dysfunction resulting in a low ejection fraction, paradoxical embolus from the venous system due to a shunt through a septal defect such as an aneurysm or patent foramen ovale, or vessel-to-vessel atheroembolism due to atherosclerotic disease in the vertebral arteries, carotid arteries, and aortic arch.
Changes in the arterial vasculature of small perforating arteries can result in narrowing of the vessel lumen and eventual occlusion. Chronic hypertension is one state that leads to vessel damage secondary to lipohyalinosis and endothelial damage. Hyperlipidemia, smoking, and diabetes also lead to changes in the vessel wall that result in decreased compliance and intraluminal stenosis. These changes often result in lacunar infarcts, which are small infarcts defined by their size (<15 mm3) and are typically located in deep structures such as the internal capsule, basal ganglia, thalamus, and pons.
Stroke of Other Determined Etiology
The majority of ischemic strokes are classified in one of the previous categories. Rarely, other causes must be investigated, particularly in patients who are young and have no risk factors for stroke. Among these causes are coagulopathies, vasculopathies, genetic disorders, and metabolic disorders.
Stroke of Undetermined Etiology
In a significant number of cases (≤40%), no clear explanation can be found for an ischemic stroke despite an extensive diagnostic evaluation. These strokes are classified as strokes of undetermined etiology, or cryptogenic strokes. This is a diagnosis of exclusion, however, and should only be made once a thorough search for both common and uncommon causes of stroke has been completed.
Transient Ischemic Attack
A transient ischemic attack (TIA) is a brief episode of neurological dysfunction caused by focal brain or retinal ischemic, with clinical symptoms typically lasting less than one hour, and without evidence of acute infarction. It is important to note that many patients with transient symptoms lasting less than 24 hours actually have associated infarction on imaging and should be classified as a stroke. Patients with TIA or mild stroke are at risk for developing stroke in the near future: 10% to 15% of patients will have a stroke within 3 months, with half occurring within 48 hours.
Intracerebral hemorrhage occurs when a blood vessel within the brain parenchyma ruptures and causes accumulation of blood within the brain tissue. Weakening of the blood vessel wall is often a result of chronic uncontrolled hypertension or a problem intrinsic to the blood vessel such as amyloid angiopathy or other vascular malformation. In hypertension, microaneurysms in perforating vessels, known as Charcot-Bouchard aneurysms, can rupture and cause bleeding. The thalamus, basal ganglia, pons, and cerebellum are the most common sites for these hypertensive bleeds. Lobar hemorrhages more commonly result from amyloid angiopathy, which is typically seen in older patients. This should be suspected when there is evidence of prior areas of hemorrhage manifested as hemosiderin deposits on magnetic resonance imaging (MRI). Other causes of intracerebral hemorrhage include the use of anticoagulants, thrombolytics, and antiplatelet agents, particularly when levels are supratherapeutic. They may also be caused by an underlying primary or metastatic brain tumor, especially when there are focal areas of necrosis within the tumor bed.
Subarachnoid hemorrhage is most commonly due to trauma and typically occurs adjacent to areas of bony prominence, such as the temporal poles and the frontal poles. Subarachnoid hemorrhage can also result from rupture of a cerebral aneurysm. Aneurysms are usually located at vulnerable branch points in the circle of Willis due to weakening of the vessel wall. The most common sites of aneurysm formation and rupture are in the distribution of the anterior communicating artery and the posterior communicating artery. Uncontrolled chronic hypertension, smoking, and a family history of aneurysms are risk factors for formation and rupture of aneurysms. In 10% to 20% of cases of spontaneous, nontraumatic subarachnoid hemorrhage, no cause is found despite serial angiography. The prognosis for these patients is typically favorable.
Signs and Symptoms
An acute stroke is signified by a sudden onset of focal neurologic deficit and is variable depending on the area of tissue ischemia. Localization can often be made by the pattern of clinical findings. Common stroke syndromes are listed in Table 2 according to vascular distribution. Although headache might accompany an ischemic stroke, an acute and severe headache that is maximal at onset more commonly represents a subarachnoid or intraparenchymal hemorrhage, especially if this is followed by somnolence or decreased mental status. Seizures can also occur at the onset of ischemic or hemorrhagic strokes.
Table 2: Overview of Selected Stroke Syndromes
|Vascular Territory||Area Affected||Signs and Symptoms|
|Anterior cerebral artery||Frontal pole and mesial frontal lobe||
|Middle cerebral artery||Posterior frontal, temporal, parietal lobes||
|Posterior cerebral artery||Occipital lobe||
|Anterior inferior cerebellar artery||Lateral pontine syndrome||
|Posterior inferior cerbellar artery||Lateral medulla (Wallenberg syndrome)||
|Basilar artery||Pons (locked-in syndrome)||
|Vertebral artery||Medial medulla||
|Vertebral artery||Lateral medulla||
Motor symptoms consist of facial droop, hemiparesis, or isolated weakness of the arm or leg. Dizziness, slurred speech, problems with coordination, or difficulty with gait and balance may also be reported and may be due to involvement of cerebellar fibers. Sensory symptoms include numbness or altered sensation, with tingling paresthesias of one side of the body or face, or both. Vision loss in one eye or both eyes as in a homonymous hemianopsia can also occur.Patients with an acute stroke might also present with confusion or are sometimes perceived as being confused when there is an expressive or receptive aphasia or a visuospatial neglect phenomenon.
One of the most urgent and potentially devastating stroke syndromes is thrombosis of the basilar artery, which can manifest with acute quadriparesis, loss of consciousness, and respiratory failure.
The first step in correctly identifying a stroke is a rapid, thorough neurologic assessment consisting of a focused history and neurologic examination. A differential diagnosis is listed in Box 1. It is of utmost importance to establish a time of symptom onset when eliciting the history from the patient or witnesses. If the patient woke with symptoms, treatment is based on the time the patient was last seen normal, which for many would be when they went to bed the night before.
|Box 1: Differential Diagnosis of Stroke|
|Complex or atypical migraine|
|Hypoglycemia or hyperglycemia|
|Meningitis, encephalitis, or systemic infection|
|Multiple sclerosis exacerbation|
Vital signs should be assessed frequently, with particular attention to blood pressure and heart rate. It is also necessary to obtain a blood glucose level immediately because both hypo- and hyperglycemia can manifest clinically with acute neurologic deficits, mimicking a stroke.
Regarding the physical examination, a variety of tools in the form of validated scales are available for evaluation of the patient at presentation. The NIH Stroke Scale is a widely accepted and useful tool that is recommended in the acute phase for the purpose of quickly identifying focal neurologic deficits and their severity (Class I, Level B recommendation).
Acute Management and Interventions
The first step in the appropriate management of acute stroke is early identification at symptom onset. Early notification of emergency medical services with use of stroke-identification algorithms, management in the field with stroke protocols, and emergent transport to the nearest center capable of treating acute stroke is recommended (Class I, Level B evidence). Airway, breathing, and circulation should be stabilized, with airway support and ventilatory assistance in the appropriate patients (Class I, Level C evidence). Initial laboratory testing and CT brain scan should be performed as detailed earlier.
In patients who present with stroke symptoms within 3 hours of 'last known well' and who meet eligibility criteria (Box 2), treatment with IV recombinant tissue plasminogen activator (rtPA) is recommended at a dose of 0.9 mg/kg (maximum dose, 90 mg) over 1 hour, with the first 10% given as a bolus over 1 minute (Class I, Level A evidence). Studies have demonstrated that 31% to 50% of patients treated with rtPA within 3 hours experienced improved recovery at 3 months as compared to 20% to 38% of patients in the placebo arm. However, strict adherence to national guidelines in the administration of rtPA and postlysis management is critical, given the 6% risk of intracranial hemorrhage. The time window for IV rtPA has been expanded more recently out to 4.5 hours from time last known well. (Class I, Level B evidence) based upon a European study The European Cooperative Acute Study III (ECASS III). In this study, 52.4% of subjects receiving IV rtPA within 3 to 4.5 hours had favorable outcome compared to 45.2% of subjects that received placebo. The eligibility criteria for treatment in the 3- to 4.5-hour time period are similar to those for persons treated at earlier time periods, but with the additional exclusion criteria (See Box 2). Although the 3- to 4.5-hour time period has been endorsed by the American Stroke Association, it has not yet been approved by the Food and Drug Administration (FDA).
|Box 2: Exclusion Criteria for Treatment of Acute Ischemic Stroke with rtPA within 3 Hours of Last Known Well|
|Onset of symptoms >3 hours|
|CT with acute hemorrhage or hypodensity involving >1/3 of the hemisphere|
|Systolic blood pressure >185 mm Hg and diastolic blood pressure >110 mm Hg|
|Evidence of active bleeding or acute trauma on exam|
|Anticoagulant therapy with INR >1.7 (or elevated PTT if receiving heparin)|
|Platelet count <100,000 mm3|
|Blood glucose <50 mg/dL|
|Seizure at symptom onset|
|History of prior intracranial hemorrhage, neoplasm, or vascular malformation|
|Head trauma or stroke in past 3 months|
|Myocardial infarction in past 3 months|
|Gastrointestinal or urinary tract hemorrhage in past 3 weeks|
|Major surgery in past 14 days|
|Arterial puncture at a noncompressible site in past 7 days|
|Rapid, spontaneous improvement of neurologic signs|
|Symptoms suggesting subarachnoid hemorrhage|
|Mild neurologic deficit|
|Additional Exclusion Criteria for Treatment within 3 to 4.5 Hours of Last Known Well|
|Age >80 years|
|Taking oral anticoagulants regardless of INR level Baseline NIHSS >25|
|History of both stroke and diabetes|
CT, computed tomography; INR, international normalized ratio; PTT, partial thromboplastin time; rtPA, recombinant tissue plasminogen activator; NIHSS, National Institutes of Health Stroke Scale.
In selected patients who are not candidates for IV rtPA therapy, intra-arterial thrombolysis by a qualified neuro-interventionalist may be considered in stroke patients who present within 6 hours of onset (Class I, Level B recommendation). However, the availability of intra-arterial thrombolysis should not preclude the administration of IV rtPA in eligible patients (Class III, Level C evidence). Endovascular intervention, including angioplasty and disruption or removal of the clot, is another option available at some specialized stroke centers for patients within 8 hours of last known well. Several devices have been approved by the FDA to recanalize occluded vessels, but guideline recommendations for mechanical revascularization are generally lacking.
Urgent anticoagulation in acute ischemic stroke is no longer recommended and should not be used to replace IV rtPA therapy in eligible patients (Class III, Level A evidence). Oral aspirin therapy at a dose of 325 mg daily is recommended 24 to 48 hours after stroke onset in most patients (Class I, Level A evidence), but it should not be given within 24 hours following rtPA therapy (Class III, Level A and B).
In patients who are eligible for rtPA, treatment of arterial hypertension is recommended (Class I, Level C evidence) with a goal blood pressure of less than 185/110 mm Hg before rTPA is administered. Close post-lysis monitoring, with antihypertensive treatment given according to the rtPA protocol, is also crucial to prevent hemorrhage (Class I, Level B evidence). In patients who are not candidates for rtPA, blood pressure management in the acute setting is still controversial, but the consensus is that antihypertensive medications should be withheld unless systolic blood pressure is higher than 220 or diastolic blood pressure is higher than 120 (Class I, Level C evidence). After 24 hours, initiation of antihypertensive agents is considered relatively safe for patients with pre-existing hypertension.
Hypoxemia should be treated with supplemental oxygen, and fever should be treated with antipyretic agents (Class I, Level C evidence). Euglycemia should be targeted, because persistent hyperglycemia has been associated with poor outcomes (Class IIa, Level C evidence).
Patients should be admitted to specialized stroke care units incorporating rehabilitation when possible (Class I, Level A evidence). Close monitoring during the first 72 to 96 hours of acute ischemic stroke is important to assess for signs of hemorrhagic transformation or brain edema (Class I, Level B evidence). Decompressive surgery in the setting of malignant edema may be life-saving, but the morbidity is unknown in the setting of major cerebral hemispheric infarctions (Class IIa, Level B evidence).
Treatment of concomitant medical illnesses, pneumonia, and urinary tract infections is recommended (Class I, Level B and C evidence). Screening swallow evaluations should be performed to assess the patientâ€™s risk for aspiration pneumonia (Class I, Level B evidence). Subcutaneous anticoagulation or sequential compression devices should be instituted to prevent formation of deep venous thrombosis, especially in patients with decreased mobility (Class I, Level A evidence). Additional early and late complications are listed in Box 3.
|Box 3: Early and Late Complications of Stroke|
|Early Complications (within 7 days)|
|Late Complications (>7 days later)|
The American Heart Association and American Stroke Association issued a guideline for the primary prevention of stroke in 2010 and one focused on the management of patients with extracranial carotid stenoses in 2011, which are summarized here.
- Each patient should undergo formal assessment of his or her stroke risk (Class I, Level A evidence).
- Hypertension has been well documented to increase the risk of stroke, and current recommendations are to perform regular screening for hypertension a (Class I, Level A evidence). Diet and lifestyle should be modified and pharmacologic treatment should be prescribed according to the JNC 7 recommendations. Currently, guidelines emphasize individualization of therapy, with the overall goal being blood pressure reduction to at least less than 140/90 mm Hg.
- In patients with diabetes, stricter blood pressure control to less than 130/80 mm Hg with use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers is recommended (Class I, Level A evidence). In these patients, a statin to lower the risk of first stroke is also recommended (Class I, Level A evidence). Tight glycemic control is encouraged to reduce microvascular complications, but evidence showing a reduction in stroke risk is lacking.
- In patients with dyslipidemia, recommendations state that those with known coronary disease and patients at high-risk for coronary disease be treated with lifestyle measures and a statin, even in the presence of a normal LDL (Class I, Level A evidence). In patients with atrial fibrillation, warfarin therapy with a target international normalized ratio of 2.0 to 3.0 is recommended in those without contraindications to oral anticoagulants (Class I, Level A evidence).
- Smoking doubles the risk of ischemic stroke and doubles or quadruples the risk of subarachnoid hemorrhage. Smoking cessation is recommended (Class I, Level B evidence) and the use of counseling, nicotine replacement, and oral medications should be considered (Class IIa, Level B evidence). In addition, it is reasonable to avoid exposure to environmental smoke (Class IIa, Level C evidence).
- Physical activity is recommended to reduce the risk of stroke (Class I, Level B evidence). Adults should engage in 2 hours and 30 minutes of moderate intensity activity each week or one hour and 15 minutes of vigorous intensity aerobic activity each week (Class I, Evidence B evidence).
- Currently, aspirin therapy is not recommended for primary stroke prevention in people at low risk for a cardiovascular event (Class III, Level A evidence), but it may be helpful in primary stroke prevention for people whose risk is sufficiently high for the benefits to outweigh the risks (a 10-year risk of cardiovascular events of 6% to 10%) (Class I, Level A evidence).
- In patients with asymptomatic carotid artery stenosis, screening for other treatable causes of stroke and aggressive control of all risk factors is recommended (Class I, Level C evidence). Aspirin therapy is recommended in the absence of contraindications (Class I, Level A evidence). Selection of asymptomatic patients for carotid revascularization should be guided by an assessment of multiple different factors and discussion of risk and benefits of the procedure (Class I, Level C evidence). Prophylactic carotid endarterectomy is reasonable in selected patients with high-grade asymptomatic carotid stenosis if the risk of perioperative complications is low (Class IIa, Level A evidence). Carotid artery angioplasty and stenting may be considered in asymptomatic patients, but its effectiveness compared with medical therapy has not been well established (Class IIb, Level B evidence). For both symptomatic and asymptomatic patients with high-grade carotid stenosis who are at high risk of complications with revascularization, the effectiveness of revascularization over medical management is also not established (Class IIb, Level B evidence).
Following a stroke, lifestyle changes should be made, with particular attention to reducing risk factors for stroke as outlined earlier. In patients with atrial fibrillation, warfarin therapy is recommended for preventing recurrent stroke in the absence of contraindications. In patients with a history of noncardioembolic ischemic stroke, antiplatelet therapy is recommended. Aspirin, clopidogrel, and dipyridamole in combination with low-dose aspirin have all been shown to be beneficial in reducing the risk of recurrent stroke in multiple clinical trials. The most recently published study, the PRoFESS trial from 2008, directly compared clopidogrel alone and dipyridamole in combination with low-dose aspirin for preventing recurrent stroke. Although the results did not meet the predefined statistical criteria for noninferiority, there was no statistically significant difference between the groups in the primary outcome of recurrent stroke. However, there was an increase in the rate of intracranial hemorrhage with the dipyridamole and aspirin arm, which was not seen in prior studies evaluating this combination. Currently there is no clear uniform recommendation of one agent over another, and therapy must be tailored to individual patients based on availability, cost, and side-effect profile.
For patients with symptomatic high-grade carotid artery stenosis, carotid endarterectomy is recommended for patients within 6 months of the stroke event if they are at average or low risk (Class I, Level A evidence). Carotid stenting is an alternative to CEA for symptomatic patients at average or low risk (Class I, Level B evidence) based upon the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), which demonstrated no significant difference in the primary outcome of stroke, death, or myocardial infarction, in symptomatic or asymptomatic patients randomized to CEA or stenting.
Considerations in Special Populations
In patients with known medical conditions that increase the risk of stroke, such as sickle cell disease, vasculitis, or cardiomyopathy, the approach to stroke prevention should be a coordinated effort among the patient, the primary care physician, and involved specialists. Often, it is important to aggressively manage the underlying disease state. The risk of ischemic stroke or intracerebral hemorrhage is 2.4 times greater during pregnancy and the first 6 weeks following delivery. Focal neurologic signs in this population merits prompt evaluation by a neurologist. Other special considerations include children or young adults with stroke and patients in whom no clear etiology of stroke is determined. Further workup may include referral to a geneticist for evaluation of potential genetic or metabolic causes of stroke in these populations.
During the hospitalization for an acute stroke, intensive speech, physical, and occupational therapy should be initiated as soon as the patient is stable enough to participate. Most functional recovery occurs within the first 3 months. After this, further recovery is possible, but it is generally limited. The 1-year mortality in first-time stroke sufferers is 14% to 24% in persons aged 40 to 69 years, and the 1-year mortality increases to 22% to 27% in patients aged 70 years and older. Following a first stroke, the mean survival for persons aged 60 to 79 years ranges from 5.4 to 7.4 years. After age 80 years, the mean survival decreases to 1.8 years for men and 3.1 years for women.
- A stroke is defined as a sudden focal loss of neurologic function due to decreased perfusion of brain tissue.
- In patients who present with stroke symptoms, a rapid, focused neurologic history and physical examination should be performed, making every attempt to establish a specific time of onset because this helps to guide further therapy.
- Patients presenting within a 4.5-hour time window of last known well should receive IV rtPA at a dose of 0.9 mg/kg (maximum dose 90 mg) after a CT brain excludes the presence of an intracranial hemorrhage and there are no other contraindications to therapy. The dose is administered over 60 minutes, with 10% of the total dose being given initially as a bolus.
- The remaining hospital course is focused on evaluating potential etiologies of stroke, preventing early complications, and performing intensive rehabilitation.
- Anticoagulation should be considered for patients with a history of cardioembolic stroke, and antiplatelet therapy should be considered for ischemic strokes of noncardiac etiology.
- Optimization of stroke risk factor reduction is critical in both primary and secondary prevention.
The recommendations on early management of adults with ischemic stroke and prevention are based on guidelines from the American Heart Association and American Stroke Association. Data regarding clinical trials in ischemic stroke are available at strokecenter.org.
- Adams HP Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups. The American Academy of Neurology affirms the value of this statement as an educational tool for neurologists [published online ahead of print April 12, 2007]. Stroke 2007; 38:1655â€“1711.
- American Heart Association. Heart Disease and Stroke Statisticsâ€”2008 Update. Dallas, TX: American Heart Association; 2008.
- Brott TG, Halperin JL, Abbara S, et al. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary [published online ahead of print January 31, 2011]. Circulation 2011; 124:489â€“532.
- Brott TG, Hobson RW II, Howard G, et al; CREST Investigators. Stenting versus endarterectomy for treatment of carotid-artery stenosis [published online ahead of print May 26, 2010]. N Engl J Med 2010; 363:11â€“23.
- del Zoppo GJ, Saver JL, Jauch EC, Adams HP Jr; on behalf of the American Heart Association Stroke Council. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: a science advisory from the American Heart Association/American Stroke Association [published online ahead of print May 28, 2009]. Stroke 2009; 40:2945â€“2948.
- Easton JD, Saver JL, Albers, GW, et al. Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease. The American Academy of Neurology affirms the value of this statement as an educational tool for neurologists [published online ahead of print May 7, 2009]. Stroke 2009; 40:2276â€“2293.
- Goldstein LB, Bushnell CD, Adams RJ, et al. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association [published online ahead of print December 2, 2010]. Stroke 2011; 42:517â€“584.
- Hacke W, Kaste M, Bluhmki E, et al; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317â€“1329.
- National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995; 333:1581â€“1587.
- North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991; 325:445â€“453.
- Sacco RL, Diener HC, Yusuf S, et al; PRoFESS Study Group. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke [published online ahead of print August 27, 2008]. N Engl J Med 2008; 359:1238â€“1251.