Daniel David Dressler, MD, MSc

Stroke is a leading cause of disability and the third leading cause of death in the United States.1 Transient ischemic attack (TIA) carries a substantial short‐term risk for stroke.1 The risk of stroke following TIA ranges from 2% to 5% within 48 hours, is 10.5% within 90 days, and ranges from 24% to 29% within 5 years.24 Among the 780,000 new or recurrent strokes that occur each year, 180,000 are recurrent attacks.1, 5 Several evidence‐based guidelines for secondary prevention of stroke are available. To reduce variability in the assessment, diagnostic evaluation, and treatment of patients with TIA in actual clinical practice and to simplify the management of TIA or ischemic stroke, this article will review the available guidelines for secondary prevention of stroke and the data from clinical trials that support these guidelines.

PATHOPHYSIOLOGY AND SUBTYPES/CLASSIFICATION

Stroke is broadly classified as hemorrhagic or ischemic stroke. Hemorrhagic stroke, including intraparenchymal and subarachnoid hemorrhage, accounts for 13% of strokes and ischemic stroke for 87%.1 Ischemic stroke is caused by inadequate cerebral blood flow as a result of either stenosis or occlusion of the vessels supplying the brain.6 The average rate of cerebral blood flow is 50 mL/100 g a minute. Flow rates below 2025 mL/100 g a minute are usually associated with cerebral impairment, and rates below 10 mL/100 g a minute are associated with irreversible brain damage.

Approximately 20% of ischemic strokes are of cardioembolic origin; 25% are a result of atherosclerotic cerebrovascular disease; 20% are a result of penetrating artery disease (lacunes); 5% are due to other causes, such as hypercoagulable states, including protein S and C deficiency, sickle cell disease, and various types of vasculitis; and 30% are cryptogenic.7, 8 Cardioembolic stroke can be a manifestation of atrial fibrillation, valvular disease, ventricular thrombi, and other cardiac conditions.9 Large arteries, such as the carotid arteries and the proximal aorta, are a source of atherogenic emboli.10 Atherosclerotic plaques in the arteries may narrow the lumen of the blood vessel or produce emboli, which results in occlusion of the distal arteries, causing a stroke.

RISK FACTORS

Several risk factors, both nonmodifiable and modifiable, predispose individuals to stroke. Nonmodifiable risk factors include age, sex, race, and family or personal history of stroke or myocardial infarction (MI).1, 5 After the age of 55, the stroke rate doubles for every 10‐year increase in age.1 African Americans have a 50% greater risk of death due to stroke than whites.1 The appropriate management of modifiable risk factors can significantly reduce the risk of recurrent stroke and improve survival. The many modifiable factors include hypertension, heart disease, smoking, diabetes, atrial fibrillation, dyslipidemia, obesity, and alcohol abuse.1, 5 The mechanisms of how these factors increase the risk for stroke and management of these factors are discussed later in this article. It is important to educate individuals, particularly those who also have nonmodifiable risk factors, about modifiable risk factors in order to enable early and appropriate intervention.

DIAGNOSIS

Most patients with TIA are asymptomatic when they present to the emergency department (ED). The risk of stroke following an episode of TIA has been found to be 3.5% within 48 hours in a meta‐analysis based on a random effects model;11 therefore, it is critical to quickly identify patients with high short‐term risk for recurrent stroke.12 The ABCD2 score was recently validated in TIA patients to estimate the near‐term risk of completed stroke.13 Patients with a score of 03 on the ABCD2 are at low risk, those with a score of 4 or 5 are at moderate risk, and those with a score 6 or 7 are at severe risk for recurrent stroke (Table 1).13 Risk scores, although highly predictive, should complement clinical judgment in the assessment of individual stroke risk.

Currently, there are no specific guidelines for the diagnostic evaluation of patients with suspected TIA. However, the following approach, including elements of acute evaluation for both stroke and TIA as well as risk factor identification that may aid in choosing specifics of secondary prevention, may be adopted in the management of patients with TIA (Table 2).14, 15

A computed tomography (CT) scan of the head or magnetic resonance imaging (MRI) of the brain should be performed as soon as possible to distinguish between ischemic and hemorrhagic stroke, eliminate other pathologies that mimic TIA or stroke, and guide selection of the appropriate treatment approach. CT scanning is often the best initial imaging choice because it reliably excludes intracranial hemorrhage and is rapidly available in most settings. For those for whom the diagnosis is uncertain, diffusion‐weighted MRI may be more helpful. Because of the time issues surrounding the use of tissue plasminogen activator, waiting for an MRI may not always be the best choice, although some institutions are now able to provide quick access to MRI imaging. Imaging can detect silent cerebral infarcts associated with an increased risk of stroke. In patients with previous TIA and/or stroke, MRI is more sensitive than CT in detecting small, old infarcts (although most are seen on CT) and in visualizing the posterior fossa (cerebellum and brain stem).12

Holter electrocardiography or inpatient telemetry monitoring can be performed to identify atrial fibrillation, a known risk factor for stroke or TIA.16 Transesophageal echocardiography (TEE) has been reported to be more sensitive than transthoracic echocardiography (TTE) for detecting cardioembolic sources of TIA or ischemic stroke across multiple age groups.17 TEE has several advantages over TTE, such as the creation of clearer images of the aorta, the pulmonary artery, valves of the heart, both atria, the atrial septum, and the left atrial appendage.

Cerebral angiography is indicated in several instances, including in children or young patients with ischemic stroke because vascular abnormalities and cerebral vasculitis are relatively more common causes in patients in these age groups.18 Furthermore, in centers in which intra‐arterial procedures are frequently performed, angiography is indicated to confirm the suspicion of posterior circulation vessel (ie, vertebral or basilar artery) occlusion prior to intervention. Angiography has the highest diagnostic validity compared with other noninvasive techniques and may be indicated if cerebral vasculitis or nonatherosclerotic disease of extracranial arteries (eg, dissections, vascular malformations) is suspected. Angiography of intracranial vessels is the gold standard for the study of cerebral aneurysms and is recommended in patients with subarachnoid hemorrhage, but there is evidence that magnetic resonance angiography (MRA) and digital subtraction angiography have better discriminatory ability in the 70%99% range of stenosis compared with duplex ultrasonography (DUS) for determining candidacy for carotid endarterectomy (CEA) or stenting.19, 20

The MRA and CT angiography (CTA) are generally used to visualize the intracranial and extracranialboth anterior and posteriorcerebral circulation. The use of MRA or CTA to image cerebral circulation has generally supplanted the use of carotid and transcranial ultrasonography and obviated the need for catheter angiography in investigating the etiology of most ischemic strokes and TIAs. The degree of carotid stenosis should be primarily estimated using noninvasive techniques (DUS, MRA, CTA).21 Duplex ultrasonography is recommended after CEA 6 months and every 1 2 years after the procedure in order to monitor recurrent stenosis.22 Angiography should be performed when the results of noninvasive examinations are discordant; when significant atherosclerotic disease of intracranial arteries is suspected, especially in vertebrobasilar arteries; or when MRA or CT angiography provides technically poor images.23

Transcranial Doppler ultrasonography and color Doppler ultrasound (TCD) are used to evaluate the intracranial vessels and may provide additional information on patency of cerebral vessels, recanalization, and collateral pathways. Compared with the gold standard of conventional angiography, TCD has a positive predictive value of 36% and a negative predictive value of 86% for a diagnosis of intracranial stenosis.24 This technique also can be used as a complementary examination in patients undergoing CEA in order to aid in preoperative evaluation and intraoperative monitoring of blood flow in the territory of the operated artery.12

TREATMENT

The management of ischemic stroke or TIA includes lifestyle modifications, reduction of modifiable risk factors, and appropriate surgical and medical intervention.12

SUMMARY OF GUIDELINES FOR SECONDARY PREVENTION OF STROKE

The AHA/ASA, American College of Chest Physicians (ACCP), and National Stroke Association (NSA) have developed and published practice guidelines for the management of TIA, with detailed information on secondary prevention of stroke.5, 79, 80 The key recommendations from these 3 organizations are summarized in Table 5 .5, 79, 80 This section summarizes the current guidelines regarding the use of antiplatelets and anticoagulants for the secondary prevention of stroke.

FUTURE DEVELOPMENTS

One of the largest stroke prevention trials currently ongoing is the Prevention Regimen for Effectively avoiding Second Strokes (PRoFESS) study. The PRoFESS trial is a large (N = 20,333), randomized, double‐blind, placebo‐controlled, multinational study comparing the efficacy and safety of aspirin plus ER‐DP with that of clopidogrel and the efficacy of telmisartan versus placebo in the presence of background blood pressure treatments in preventing recurrent stroke.86 The primary outcome of the study is time to first recurrent stroke. Recently, the baseline demographics were published.86 The mean age of patients was 66.1 years at enrollment, 36% of patients were women, and mean time from event to randomization was 15 days (40% randomized within 10 days). Most participants had had a stroke of arterial origin (29% large vessel disease and 52% small vessel disease), whereas 2% had had a stroke due to cardioembolism and 18% due to other causes. These baseline data suggest that the trial involves a representative international population of patients with stroke. The PRoFESS trial will provide additional insight into the benefits of the combination of aspirin plus ER‐DP for secondary prevention of stroke in addition to providing direct comparison of efficacy with clopidogrel. The latest information on this and other ongoing stroke prevention trials can be accessed at http://www.strokecenter.org/trials/.

Stroke is a leading cause of disability and the third leading cause of death in the United States.1 Transient ischemic attack (TIA) carries a substantial short‐term risk for stroke.1 The risk of stroke following TIA ranges from 2% to 5% within 48 hours, is 10.5% within 90 days, and ranges from 24% to 29% within 5 years.24 Among the 780,000 new or recurrent strokes that occur each year, 180,000 are recurrent attacks.1, 5 Several evidence‐based guidelines for secondary prevention of stroke are available. To reduce variability in the assessment, diagnostic evaluation, and treatment of patients with TIA in actual clinical practice and to simplify the management of TIA or ischemic stroke, this article will review the available guidelines for secondary prevention of stroke and the data from clinical trials that support these guidelines.

PATHOPHYSIOLOGY AND SUBTYPES/CLASSIFICATION

Stroke is broadly classified as hemorrhagic or ischemic stroke. Hemorrhagic stroke, including intraparenchymal and subarachnoid hemorrhage, accounts for 13% of strokes and ischemic stroke for 87%.1 Ischemic stroke is caused by inadequate cerebral blood flow as a result of either stenosis or occlusion of the vessels supplying the brain.6 The average rate of cerebral blood flow is 50 mL/100 g a minute. Flow rates below 2025 mL/100 g a minute are usually associated with cerebral impairment, and rates below 10 mL/100 g a minute are associated with irreversible brain damage.

Approximately 20% of ischemic strokes are of cardioembolic origin; 25% are a result of atherosclerotic cerebrovascular disease; 20% are a result of penetrating artery disease (lacunes); 5% are due to other causes, such as hypercoagulable states, including protein S and C deficiency, sickle cell disease, and various types of vasculitis; and 30% are cryptogenic.7, 8 Cardioembolic stroke can be a manifestation of atrial fibrillation, valvular disease, ventricular thrombi, and other cardiac conditions.9 Large arteries, such as the carotid arteries and the proximal aorta, are a source of atherogenic emboli.10 Atherosclerotic plaques in the arteries may narrow the lumen of the blood vessel or produce emboli, which results in occlusion of the distal arteries, causing a stroke.

RISK FACTORS

Several risk factors, both nonmodifiable and modifiable, predispose individuals to stroke. Nonmodifiable risk factors include age, sex, race, and family or personal history of stroke or myocardial infarction (MI).1, 5 After the age of 55, the stroke rate doubles for every 10‐year increase in age.1 African Americans have a 50% greater risk of death due to stroke than whites.1 The appropriate management of modifiable risk factors can significantly reduce the risk of recurrent stroke and improve survival. The many modifiable factors include hypertension, heart disease, smoking, diabetes, atrial fibrillation, dyslipidemia, obesity, and alcohol abuse.1, 5 The mechanisms of how these factors increase the risk for stroke and management of these factors are discussed later in this article. It is important to educate individuals, particularly those who also have nonmodifiable risk factors, about modifiable risk factors in order to enable early and appropriate intervention.

DIAGNOSIS

Most patients with TIA are asymptomatic when they present to the emergency department (ED). The risk of stroke following an episode of TIA has been found to be 3.5% within 48 hours in a meta‐analysis based on a random effects model;11 therefore, it is critical to quickly identify patients with high short‐term risk for recurrent stroke.12 The ABCD2 score was recently validated in TIA patients to estimate the near‐term risk of completed stroke.13 Patients with a score of 03 on the ABCD2 are at low risk, those with a score of 4 or 5 are at moderate risk, and those with a score 6 or 7 are at severe risk for recurrent stroke (Table 1).13 Risk scores, although highly predictive, should complement clinical judgment in the assessment of individual stroke risk.

Currently, there are no specific guidelines for the diagnostic evaluation of patients with suspected TIA. However, the following approach, including elements of acute evaluation for both stroke and TIA as well as risk factor identification that may aid in choosing specifics of secondary prevention, may be adopted in the management of patients with TIA (Table 2).14, 15

A computed tomography (CT) scan of the head or magnetic resonance imaging (MRI) of the brain should be performed as soon as possible to distinguish between ischemic and hemorrhagic stroke, eliminate other pathologies that mimic TIA or stroke, and guide selection of the appropriate treatment approach. CT scanning is often the best initial imaging choice because it reliably excludes intracranial hemorrhage and is rapidly available in most settings. For those for whom the diagnosis is uncertain, diffusion‐weighted MRI may be more helpful. Because of the time issues surrounding the use of tissue plasminogen activator, waiting for an MRI may not always be the best choice, although some institutions are now able to provide quick access to MRI imaging. Imaging can detect silent cerebral infarcts associated with an increased risk of stroke. In patients with previous TIA and/or stroke, MRI is more sensitive than CT in detecting small, old infarcts (although most are seen on CT) and in visualizing the posterior fossa (cerebellum and brain stem).12

Holter electrocardiography or inpatient telemetry monitoring can be performed to identify atrial fibrillation, a known risk factor for stroke or TIA.16 Transesophageal echocardiography (TEE) has been reported to be more sensitive than transthoracic echocardiography (TTE) for detecting cardioembolic sources of TIA or ischemic stroke across multiple age groups.17 TEE has several advantages over TTE, such as the creation of clearer images of the aorta, the pulmonary artery, valves of the heart, both atria, the atrial septum, and the left atrial appendage.

Cerebral angiography is indicated in several instances, including in children or young patients with ischemic stroke because vascular abnormalities and cerebral vasculitis are relatively more common causes in patients in these age groups.18 Furthermore, in centers in which intra‐arterial procedures are frequently performed, angiography is indicated to confirm the suspicion of posterior circulation vessel (ie, vertebral or basilar artery) occlusion prior to intervention. Angiography has the highest diagnostic validity compared with other noninvasive techniques and may be indicated if cerebral vasculitis or nonatherosclerotic disease of extracranial arteries (eg, dissections, vascular malformations) is suspected. Angiography of intracranial vessels is the gold standard for the study of cerebral aneurysms and is recommended in patients with subarachnoid hemorrhage, but there is evidence that magnetic resonance angiography (MRA) and digital subtraction angiography have better discriminatory ability in the 70%99% range of stenosis compared with duplex ultrasonography (DUS) for determining candidacy for carotid endarterectomy (CEA) or stenting.19, 20

The MRA and CT angiography (CTA) are generally used to visualize the intracranial and extracranialboth anterior and posteriorcerebral circulation. The use of MRA or CTA to image cerebral circulation has generally supplanted the use of carotid and transcranial ultrasonography and obviated the need for catheter angiography in investigating the etiology of most ischemic strokes and TIAs. The degree of carotid stenosis should be primarily estimated using noninvasive techniques (DUS, MRA, CTA).21 Duplex ultrasonography is recommended after CEA 6 months and every 1 2 years after the procedure in order to monitor recurrent stenosis.22 Angiography should be performed when the results of noninvasive examinations are discordant; when significant atherosclerotic disease of intracranial arteries is suspected, especially in vertebrobasilar arteries; or when MRA or CT angiography provides technically poor images.23

Transcranial Doppler ultrasonography and color Doppler ultrasound (TCD) are used to evaluate the intracranial vessels and may provide additional information on patency of cerebral vessels, recanalization, and collateral pathways. Compared with the gold standard of conventional angiography, TCD has a positive predictive value of 36% and a negative predictive value of 86% for a diagnosis of intracranial stenosis.24 This technique also can be used as a complementary examination in patients undergoing CEA in order to aid in preoperative evaluation and intraoperative monitoring of blood flow in the territory of the operated artery.12

TREATMENT

The management of ischemic stroke or TIA includes lifestyle modifications, reduction of modifiable risk factors, and appropriate surgical and medical intervention.12

SUMMARY OF GUIDELINES FOR SECONDARY PREVENTION OF STROKE

The AHA/ASA, American College of Chest Physicians (ACCP), and National Stroke Association (NSA) have developed and published practice guidelines for the management of TIA, with detailed information on secondary prevention of stroke.5, 79, 80 The key recommendations from these 3 organizations are summarized in Table 5 .5, 79, 80 This section summarizes the current guidelines regarding the use of antiplatelets and anticoagulants for the secondary prevention of stroke.

FUTURE DEVELOPMENTS

One of the largest stroke prevention trials currently ongoing is the Prevention Regimen for Effectively avoiding Second Strokes (PRoFESS) study. The PRoFESS trial is a large (N = 20,333), randomized, double‐blind, placebo‐controlled, multinational study comparing the efficacy and safety of aspirin plus ER‐DP with that of clopidogrel and the efficacy of telmisartan versus placebo in the presence of background blood pressure treatments in preventing recurrent stroke.86 The primary outcome of the study is time to first recurrent stroke. Recently, the baseline demographics were published.86 The mean age of patients was 66.1 years at enrollment, 36% of patients were women, and mean time from event to randomization was 15 days (40% randomized within 10 days). Most participants had had a stroke of arterial origin (29% large vessel disease and 52% small vessel disease), whereas 2% had had a stroke due to cardioembolism and 18% due to other causes. These baseline data suggest that the trial involves a representative international population of patients with stroke. The PRoFESS trial will provide additional insight into the benefits of the combination of aspirin plus ER‐DP for secondary prevention of stroke in addition to providing direct comparison of efficacy with clopidogrel. The latest information on this and other ongoing stroke prevention trials can be accessed at http://www.strokecenter.org/trials/.

Stroke is a leading cause of disability and the third leading cause of death in the United States.1 Transient ischemic attack (TIA) carries a substantial short‐term risk for stroke.1 The risk of stroke following TIA ranges from 2% to 5% within 48 hours, is 10.5% within 90 days, and ranges from 24% to 29% within 5 years.24 Among the 780,000 new or recurrent strokes that occur each year, 180,000 are recurrent attacks.1, 5 Several evidence‐based guidelines for secondary prevention of stroke are available. To reduce variability in the assessment, diagnostic evaluation, and treatment of patients with TIA in actual clinical practice and to simplify the management of TIA or ischemic stroke, this article will review the available guidelines for secondary prevention of stroke and the data from clinical trials that support these guidelines.

PATHOPHYSIOLOGY AND SUBTYPES/CLASSIFICATION

Stroke is broadly classified as hemorrhagic or ischemic stroke. Hemorrhagic stroke, including intraparenchymal and subarachnoid hemorrhage, accounts for 13% of strokes and ischemic stroke for 87%.1 Ischemic stroke is caused by inadequate cerebral blood flow as a result of either stenosis or occlusion of the vessels supplying the brain.6 The average rate of cerebral blood flow is 50 mL/100 g a minute. Flow rates below 2025 mL/100 g a minute are usually associated with cerebral impairment, and rates below 10 mL/100 g a minute are associated with irreversible brain damage.

Approximately 20% of ischemic strokes are of cardioembolic origin; 25% are a result of atherosclerotic cerebrovascular disease; 20% are a result of penetrating artery disease (lacunes); 5% are due to other causes, such as hypercoagulable states, including protein S and C deficiency, sickle cell disease, and various types of vasculitis; and 30% are cryptogenic.7, 8 Cardioembolic stroke can be a manifestation of atrial fibrillation, valvular disease, ventricular thrombi, and other cardiac conditions.9 Large arteries, such as the carotid arteries and the proximal aorta, are a source of atherogenic emboli.10 Atherosclerotic plaques in the arteries may narrow the lumen of the blood vessel or produce emboli, which results in occlusion of the distal arteries, causing a stroke.

RISK FACTORS

Several risk factors, both nonmodifiable and modifiable, predispose individuals to stroke. Nonmodifiable risk factors include age, sex, race, and family or personal history of stroke or myocardial infarction (MI).1, 5 After the age of 55, the stroke rate doubles for every 10‐year increase in age.1 African Americans have a 50% greater risk of death due to stroke than whites.1 The appropriate management of modifiable risk factors can significantly reduce the risk of recurrent stroke and improve survival. The many modifiable factors include hypertension, heart disease, smoking, diabetes, atrial fibrillation, dyslipidemia, obesity, and alcohol abuse.1, 5 The mechanisms of how these factors increase the risk for stroke and management of these factors are discussed later in this article. It is important to educate individuals, particularly those who also have nonmodifiable risk factors, about modifiable risk factors in order to enable early and appropriate intervention.

DIAGNOSIS

Most patients with TIA are asymptomatic when they present to the emergency department (ED). The risk of stroke following an episode of TIA has been found to be 3.5% within 48 hours in a meta‐analysis based on a random effects model;11 therefore, it is critical to quickly identify patients with high short‐term risk for recurrent stroke.12 The ABCD2 score was recently validated in TIA patients to estimate the near‐term risk of completed stroke.13 Patients with a score of 03 on the ABCD2 are at low risk, those with a score of 4 or 5 are at moderate risk, and those with a score 6 or 7 are at severe risk for recurrent stroke (Table 1).13 Risk scores, although highly predictive, should complement clinical judgment in the assessment of individual stroke risk.

Currently, there are no specific guidelines for the diagnostic evaluation of patients with suspected TIA. However, the following approach, including elements of acute evaluation for both stroke and TIA as well as risk factor identification that may aid in choosing specifics of secondary prevention, may be adopted in the management of patients with TIA (Table 2).14, 15

A computed tomography (CT) scan of the head or magnetic resonance imaging (MRI) of the brain should be performed as soon as possible to distinguish between ischemic and hemorrhagic stroke, eliminate other pathologies that mimic TIA or stroke, and guide selection of the appropriate treatment approach. CT scanning is often the best initial imaging choice because it reliably excludes intracranial hemorrhage and is rapidly available in most settings. For those for whom the diagnosis is uncertain, diffusion‐weighted MRI may be more helpful. Because of the time issues surrounding the use of tissue plasminogen activator, waiting for an MRI may not always be the best choice, although some institutions are now able to provide quick access to MRI imaging. Imaging can detect silent cerebral infarcts associated with an increased risk of stroke. In patients with previous TIA and/or stroke, MRI is more sensitive than CT in detecting small, old infarcts (although most are seen on CT) and in visualizing the posterior fossa (cerebellum and brain stem).12

Holter electrocardiography or inpatient telemetry monitoring can be performed to identify atrial fibrillation, a known risk factor for stroke or TIA.16 Transesophageal echocardiography (TEE) has been reported to be more sensitive than transthoracic echocardiography (TTE) for detecting cardioembolic sources of TIA or ischemic stroke across multiple age groups.17 TEE has several advantages over TTE, such as the creation of clearer images of the aorta, the pulmonary artery, valves of the heart, both atria, the atrial septum, and the left atrial appendage.

Cerebral angiography is indicated in several instances, including in children or young patients with ischemic stroke because vascular abnormalities and cerebral vasculitis are relatively more common causes in patients in these age groups.18 Furthermore, in centers in which intra‐arterial procedures are frequently performed, angiography is indicated to confirm the suspicion of posterior circulation vessel (ie, vertebral or basilar artery) occlusion prior to intervention. Angiography has the highest diagnostic validity compared with other noninvasive techniques and may be indicated if cerebral vasculitis or nonatherosclerotic disease of extracranial arteries (eg, dissections, vascular malformations) is suspected. Angiography of intracranial vessels is the gold standard for the study of cerebral aneurysms and is recommended in patients with subarachnoid hemorrhage, but there is evidence that magnetic resonance angiography (MRA) and digital subtraction angiography have better discriminatory ability in the 70%99% range of stenosis compared with duplex ultrasonography (DUS) for determining candidacy for carotid endarterectomy (CEA) or stenting.19, 20

The MRA and CT angiography (CTA) are generally used to visualize the intracranial and extracranialboth anterior and posteriorcerebral circulation. The use of MRA or CTA to image cerebral circulation has generally supplanted the use of carotid and transcranial ultrasonography and obviated the need for catheter angiography in investigating the etiology of most ischemic strokes and TIAs. The degree of carotid stenosis should be primarily estimated using noninvasive techniques (DUS, MRA, CTA).21 Duplex ultrasonography is recommended after CEA 6 months and every 1 2 years after the procedure in order to monitor recurrent stenosis.22 Angiography should be performed when the results of noninvasive examinations are discordant; when significant atherosclerotic disease of intracranial arteries is suspected, especially in vertebrobasilar arteries; or when MRA or CT angiography provides technically poor images.23

Transcranial Doppler ultrasonography and color Doppler ultrasound (TCD) are used to evaluate the intracranial vessels and may provide additional information on patency of cerebral vessels, recanalization, and collateral pathways. Compared with the gold standard of conventional angiography, TCD has a positive predictive value of 36% and a negative predictive value of 86% for a diagnosis of intracranial stenosis.24 This technique also can be used as a complementary examination in patients undergoing CEA in order to aid in preoperative evaluation and intraoperative monitoring of blood flow in the territory of the operated artery.12

TREATMENT

The management of ischemic stroke or TIA includes lifestyle modifications, reduction of modifiable risk factors, and appropriate surgical and medical intervention.12

SUMMARY OF GUIDELINES FOR SECONDARY PREVENTION OF STROKE

The AHA/ASA, American College of Chest Physicians (ACCP), and National Stroke Association (NSA) have developed and published practice guidelines for the management of TIA, with detailed information on secondary prevention of stroke.5, 79, 80 The key recommendations from these 3 organizations are summarized in Table 5 .5, 79, 80 This section summarizes the current guidelines regarding the use of antiplatelets and anticoagulants for the secondary prevention of stroke.

FUTURE DEVELOPMENTS

One of the largest stroke prevention trials currently ongoing is the Prevention Regimen for Effectively avoiding Second Strokes (PRoFESS) study. The PRoFESS trial is a large (N = 20,333), randomized, double‐blind, placebo‐controlled, multinational study comparing the efficacy and safety of aspirin plus ER‐DP with that of clopidogrel and the efficacy of telmisartan versus placebo in the presence of background blood pressure treatments in preventing recurrent stroke.86 The primary outcome of the study is time to first recurrent stroke. Recently, the baseline demographics were published.86 The mean age of patients was 66.1 years at enrollment, 36% of patients were women, and mean time from event to randomization was 15 days (40% randomized within 10 days). Most participants had had a stroke of arterial origin (29% large vessel disease and 52% small vessel disease), whereas 2% had had a stroke due to cardioembolism and 18% due to other causes. These baseline data suggest that the trial involves a representative international population of patients with stroke. The PRoFESS trial will provide additional insight into the benefits of the combination of aspirin plus ER‐DP for secondary prevention of stroke in addition to providing direct comparison of efficacy with clopidogrel. The latest information on this and other ongoing stroke prevention trials can be accessed at http://www.strokecenter.org/trials/.

Despite the considerable national attention drawn to the need for improved secondary stroke prevention, a gap remains between evidence and application for stroke and other vascular events. Experience with the Coverdell stroke registry has shown that a minority of acute stroke patients receive the care recommended in established guidelines.1 Data collected from 4 registry centers in the United States showed a consistent lack of appropriate diagnostics, patient education, and initiation of drug therapies proven to reduce the risk of recurrent stroke.1

According to a report from the Committee on the Quality of Healthcare in America published in 2001, suboptimal treatment as well as inefficient use of health resources can be largely attributed to fragmentation of health care delivery in the management of various diseases in the United States.2 In response to these findings, the American Stroke Association (ASA) has established recommendations for the development of stroke systems of care. The objective of a systems approach is to integrate preventive and treatment services and provide patients with evidence‐based care.3

During hospitalization for acute stroke, immediate treatment must focus on minimizing stroke progression, avoiding common complications, and preventing recurrent stroke. Prior to discharge, patients need to be educated about the importance of lifestyle modifications and pharmacotherapies to reduce their risk of a recurrence of the stroke and other atherosclerotic vascular events.3 As the physicians who focus on inpatient care, hospitalists are likely to be responsible for participating in and coordinating the multidisciplinary team that provides treatment and services to stroke patients. Hospitalists also must facilitate the transition from inpatient to outpatient care. Hospitalists are in a position to help educate stroke patients about prevention strategies throughout the hospitalization period. These functions provide hospitalists with the opportunity to lead, coordinate, and participate in stroke systems care at their institutions.

The present article discusses the components of stroke systems care recommended by the ASA and the best‐practices recommendations from the recent hospitalist roundtable discussion on routine acute stroke care. The national treatment guidelines and clinical trials supporting the recommendations of the hospitalist roundtable participants have been discussed in the article in this supplement by Dr. Likosky et al, as well as in the patient scenarios article in this supplement by Dr. Lee et al. Some of the anticipated barriers and pitfalls that may be encountered, along with potential solutions, are also discussed. Hospitalists may be able to use this review to adapt feasible components of the systems care for stroke management to improve care at their institutions.

WHAT IS STROKE SYSTEMS CARE?

A stroke system is coordinated stroke care along the entire continuum from primary prevention to rehabilitation. Postemergency department inpatient care for patients with acute stroke, also referred to as subacute care, is only one component of the community‐based stroke systems of care recommended by the ASA (Fig. 1).3 In this model, regional stroke systems identify hospitals that are acute stroke capable and determine that those institutions use clinical pathways that reflect well‐established standards of care and nationally recognized guidelines.3 In this broad sense of the term, stroke systems function to organize and coordinate the various agencies and health care providers responsible for caring for patients with stroke, from the first call to emergency services through postdischarge medical care and rehabilitation (Table 1). The subacute phase of care provides the bridge from management of the medical emergency to discharge and is central to secondary stroke prevention.

Figure 1

RATIONALE FOR HOSPITAL‐BASED STROKE SYSTEMS

The Preventing Recurrence of Thrombo‐embolic Events through Coordinated Treatment (PROTECT) program provides proof of concept.4 The PROTECT program was implemented at a large teaching hospital to improve diagnosis, treatment, and secondary prevention for patients with ischemic stroke.4 Four medication goals and instruction in 4 lifestyle interventions were chosen as indicators of program impact. In the first year after PROTECT was started, 100% of eligible patients received instruction in all 4 areas of lifestyle change prior to discharge.4 In the year following implementation of PROTECT, the rate of appropriate prescribing of antithrombotics was 98%. Appropriate prescribing of angiotensin‐converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), statins, and thiazide diuretics was significantly increased from pre‐PROTECT levels.4 After 3 months of follow‐up, patient adherence to therapy remained high.5 The final results of the PROTECT program are not yet available; however, it is reasonable to expect that increased use of evidence‐based therapy and good patient adherence to these proven therapies will have led to better patient outcomes, including lower rates of recurrent stroke.

Patient outcomes data are available for a related initiative for treatment of patients hospitalized with myocardial infarction. Compared with the year prior to implementation of the Cardiac Hospitalization Atherosclerotic Management Program (CHAMP), more patients who were involved in the CHAMP intervention achieved low‐density lipoprotein cholesterol levels P < .001). In addition, these patients achieved a 57% reduction in recurrent myocardial infarction.6

These 2 studies indicate a benefit of establishing hospital‐based stroke systems; however, these studies are the initial steps, and each has limitations. For example, neither study was a prospective, randomized trial with a concurrent control group.4, 6 In addition, PROTECT data were not evaluated by independent audit but by individuals who were aware of the program goals, and limited data were available regarding contraindications to therapy.4 CHAMP did not assess adherence to nonpharmacologic interventions or the effect of surgical interventions.6 Large, randomized, controlled trials are needed to better understand the impact of such systems. Although larger evidence‐based trials are needed, it is important to review available information on stroke systems to adapt those components that align with each institution's available resources.

ESTABLISHING HOSPITAL‐BASED STROKE SYSTEMS

Several barriers exist to establishing a stroke systems care program, as detailed in Table 2. The support and involvement of the hospital administration is essential to success, as is multidisciplinary agreement that such a program will benefit patients.

Other potential points of resistance revolve around the financial impact of implementing a stroke systems approach to care. The proposed stroke systems care plan is consistent with meeting nationally recognized quality improvement standards; however, the current health care market forces demand accountability for health care expenditures. Increasingly, payers are turning to the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) and the National Committee for Quality Assurance (NCQA) evaluations to determine quality of care at various institutions. These programs encourage the use of standardized treatment protocols consistent with the concept of systems approach to care. Moreover, stroke care is a JCAHO quality measure and thus may have a financial impact on hospitals. It is possible that implementing standardized procedures for stroke care may reduce the cost of care. Information about the JCAHO Disease Specific Certification for Acute Stroke Care can be accessed at http://www.jointcommission.org/.7

Once there is agreement that a stroke system should be developed, a multidisciplinary team should be established. A multidisciplinary team may include hospitalists, neurologists, neurosurgeons, emergency medicine physicians, diagnostic and interventional radiologists, nurses, physiotherapists, occupational therapists, speech and language therapists, and social workers. However, the components of the multidisciplinary team may vary depending on the available staff and financial resources at different stroke centers. Assuring all participants in the system that their input is valued can improve communication among stroke specialists, hospitalists, and primary care clinicians. This team is responsible for evaluation of current procedures and development of algorithms, discharge forms, patient education, and preprinted orders.

The task of developing a cohesive plan for stroke care may appear onerous. Existing diagnostic and treatment procedures may be poorly designed or organized. However, multiple online sources provide tools for every aspect of stroke systems care. Information about evidence‐based stroke care practices is available as part of the American Heart Association (AHA)/ASA Get with the GuidelinesStroke program and can be accessed at http://www.strokeassociation.org.8 Standardized admission orders, patient education materials, and data‐monitoring methods are available at this site. Hospitalist‐specific information may also be found in the Stroke Resource Room of the Society of Hospital Medicine Web site (http://www.hospitalmedicine.org).9 A similar array of tools can be found at the PROTECT Web site (http://strokeprotect.mednet.ucla.edu).10 These materials are designed to facilitate integration of secondary prevention practices into stroke systems care.

A stroke system of care is a dynamic process. The multidisciplinary team may also be responsible for continuous monitoring and reporting of the efficiency and impact of the system and providing feedback to other staff and administration. Protocols should be revised regularly to account for new evidence‐based treatments and to streamline their use. The Canadian Stroke Systems Coalition recommends that a comprehensive and efficient system include prevention, prehospital and emergency care, hospital care, rehabilitation, reintegration into the community, surveillance, and research.11 Hospital staff should be educated in core competencies in hospital medicine as well as any changes to protocols made over time. Protocols that facilitate communication among health care providers should also be developed, and hospitalists may play a central role in this process. Accurate and timely transfer of patient information from the emergency department to the stroke center or ward is imperative.

FOCUSING ON INPATIENT CARE

Clinical pathways for inpatient care should be designed to limit stroke progression as much as possible.3 The Brain Attack Coalition (BAC) provides a resource for clinical pathways implemented at various institutes in the United States, including the Stanford Stroke Center, the Cleveland Clinic Foundation, and Thomas Jefferson University Hospital, among others (http://stroke‐site.org/pathways/pathways.html).12 Between 30% and 40% of acute stroke patients will show signs of stroke progression in the first week following stroke onset. Stroke can affect multiple systems, and symptom progression as a result of cerebral edema, hemorrhagic conversion, or additional strokes may require surgical intervention and warrants consultation with a neurologist.13

A neurologist should be available to the stroke system patients at all times, and ideally, all acute stroke patients should be evaluated by a neurologist specializing in the evaluation and treatment of patients with stroke.14 There are several stroke scales available to evaluate stroke patients, including the Barthel Index, the Glasgow outcome scale, the Modified Rankin Scale, the National Institutes of Health Stroke Scale, and the Hunt and Hess Classification of Subarachnoid Hemorrhage (http:// www.stroke‐site.org/stroke_scales/stroke_scales. html).15 These scales aid in the assessment of severity of stroke and may be helpful for hospitalists and other health care providers to recognize when a neurology consult is needed. The team should agree on criteria that indicate a neurological emergency, such as stroke progression, and other reasons for immediate consultation with a neurologist, such as worsening of stroke, stroke in a young patient, or uncertain diagnosis. These criteria should be included as an established part of the clinical pathway.

Common complications of stroke, such as myocardial infarction, deep vein thrombosis, pulmonary embolism, urinary tract infections, aspiration pneumonia, dehydration, poor nutrition, skin breakdown, and metabolic disorders, should be anticipated, and preventive steps should be taken. The measures to prevent the above complications of stroke need to be initiated in the emergency department.3

Management of existing comorbid conditions is another key part of subacute stroke care. Given that 85% of all hospitalists have a background in internal medicine, management of comorbid conditions such as diabetes and hypertension is an area in which hospitalists have professional competence. Patient history and use of prescription medications prior to stroke should be reviewed whenever possible and incorporated into short‐term and long‐term treatment plans. Patients with diabetes in particular may benefit more from rigorous control of blood pressure and lipids compared with other patients.16

Secondary stroke prevention should start as early as considered safe. Diagnosis of stroke subtype, often accomplished in the emergency department, establishes suitability for antithrombotics and optimal management strategy. Patients who receive a diagnosis of stroke secondary to cardioembolic atrial fibrillation should be treated with an anticoagulant after the acute period. Aspirin can be used for those individuals unable to use anticoagulants.16 For those individuals with stroke of noncardioembolic origin, particularly those with atherosclerosis and lacunar or cryptogenic infarcts, antiplatelet agents are recommended.14

A multimodal prevention strategy is recommended to manage blood pressure and dyslipidemia poststroke. An algorithm for managing blood pressure soon after stroke has been developed by the PROTECT program (Fig. 2).10 Antihypertensives, usually a combination of an ACE inhibitor and a thiazide diuretic, can be initiated at low doses 48‐72 hours after stroke. A longer delay is recommended for patients with large infarcts or evidence of uncontrolled hypertension. ARBs may be substituted for ACE inhibitors.10 Target blood pressures should be determined using the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.17 In general, even a reduction of 10/5 mm Hg has been shown to be beneficial.16

Figure 2

Statins are recommended for all patients with elevated serum lipids unless treatment with statins is contraindicated. The recommended target level for low‐density lipoprotein cholesterol is below 100 mg/dL for individuals with coronary heart disease and symptomatic atherosclerosis. A target below 70 mg/dL may be appropriate for patients at very high risk.16

Prior to discharge, patients or their caregivers should be given prescriptions adequate to cover the time until postdischarge follow‐up visit. The responsible persons need to be made aware that some medications such as antihypertensives will require dosage adjustments by an outpatient physician, and the timing of the follow‐up visit may need to be arranged accordingly.

The importance of stroke risk reduction should be part of predischarge patient education, along with a list of the warning signs of stroke. Adherence to the treatment regimen, including lifestyle changes and medications, should be emphasized. Patients or their caregivers should be educated about identifying adverse events and a plan to address them. Understanding that some adverse effects (eg, headache with aspirin plus extended‐release dipyridamole) are likely to be transient may prevent unnecessary discontinuation of treatment and reduce anxiety.

Patient and caregiver education can be reinforced by providing standardized patient education materials that can be found in the Stroke Resource Room at the Society of Hospital Medicine Web site (http://www.hospitalmedicine.org),9 PROTECT (http://strokeprotect.mednet.ucla.edu),10 ASA (http://www.strokeassociation.org),8 and AHA (http://www.americanheart.org)18 Web sites.

Transfer of patient information to outpatient health care providers is a critical step in stroke systems care. Notes indicating any need for medication dose adjustment must be included. Discharge summaries should be available to primary care providers, neurologists, and rehabilitation specialists prior to follow‐up visits. The use of electronic forms that can be faxed or sent by E‐mail can shorten delivery time considerably. In lieu of electronic delivery, physician letters can be used, and prototypes are available at the resource Web sites. Whenever possible, a follow‐up phone call to the primary care physician provides the best means to ensure clear communication.

SUMMARY

Hospitalists are well qualified to lead quality focused patient care initiatives at their institutions. Use of standardized protocols to reduce the risk of secondary stroke is proven to increase appropriate prescribing at discharge, which in turn improves patient adherence to evidence‐based therapy. Multidisciplinary communication, including communication with outpatient clinicians, facilitates the transition from inpatient to outpatient health care providers.

In addition to improving patient care, use of standardized protocols is tracked by JCAHO and offers assurance to payers that a particular hospital and its staff are committed to quality care. Establishing protocols is made relatively easy by the online availability of materials that can be adapted to various hospital settings.

Despite the considerable national attention drawn to the need for improved secondary stroke prevention, a gap remains between evidence and application for stroke and other vascular events. Experience with the Coverdell stroke registry has shown that a minority of acute stroke patients receive the care recommended in established guidelines.1 Data collected from 4 registry centers in the United States showed a consistent lack of appropriate diagnostics, patient education, and initiation of drug therapies proven to reduce the risk of recurrent stroke.1

According to a report from the Committee on the Quality of Healthcare in America published in 2001, suboptimal treatment as well as inefficient use of health resources can be largely attributed to fragmentation of health care delivery in the management of various diseases in the United States.2 In response to these findings, the American Stroke Association (ASA) has established recommendations for the development of stroke systems of care. The objective of a systems approach is to integrate preventive and treatment services and provide patients with evidence‐based care.3

During hospitalization for acute stroke, immediate treatment must focus on minimizing stroke progression, avoiding common complications, and preventing recurrent stroke. Prior to discharge, patients need to be educated about the importance of lifestyle modifications and pharmacotherapies to reduce their risk of a recurrence of the stroke and other atherosclerotic vascular events.3 As the physicians who focus on inpatient care, hospitalists are likely to be responsible for participating in and coordinating the multidisciplinary team that provides treatment and services to stroke patients. Hospitalists also must facilitate the transition from inpatient to outpatient care. Hospitalists are in a position to help educate stroke patients about prevention strategies throughout the hospitalization period. These functions provide hospitalists with the opportunity to lead, coordinate, and participate in stroke systems care at their institutions.

The present article discusses the components of stroke systems care recommended by the ASA and the best‐practices recommendations from the recent hospitalist roundtable discussion on routine acute stroke care. The national treatment guidelines and clinical trials supporting the recommendations of the hospitalist roundtable participants have been discussed in the article in this supplement by Dr. Likosky et al, as well as in the patient scenarios article in this supplement by Dr. Lee et al. Some of the anticipated barriers and pitfalls that may be encountered, along with potential solutions, are also discussed. Hospitalists may be able to use this review to adapt feasible components of the systems care for stroke management to improve care at their institutions.

WHAT IS STROKE SYSTEMS CARE?

A stroke system is coordinated stroke care along the entire continuum from primary prevention to rehabilitation. Postemergency department inpatient care for patients with acute stroke, also referred to as subacute care, is only one component of the community‐based stroke systems of care recommended by the ASA (Fig. 1).3 In this model, regional stroke systems identify hospitals that are acute stroke capable and determine that those institutions use clinical pathways that reflect well‐established standards of care and nationally recognized guidelines.3 In this broad sense of the term, stroke systems function to organize and coordinate the various agencies and health care providers responsible for caring for patients with stroke, from the first call to emergency services through postdischarge medical care and rehabilitation (Table 1). The subacute phase of care provides the bridge from management of the medical emergency to discharge and is central to secondary stroke prevention.

Figure 1

RATIONALE FOR HOSPITAL‐BASED STROKE SYSTEMS

The Preventing Recurrence of Thrombo‐embolic Events through Coordinated Treatment (PROTECT) program provides proof of concept.4 The PROTECT program was implemented at a large teaching hospital to improve diagnosis, treatment, and secondary prevention for patients with ischemic stroke.4 Four medication goals and instruction in 4 lifestyle interventions were chosen as indicators of program impact. In the first year after PROTECT was started, 100% of eligible patients received instruction in all 4 areas of lifestyle change prior to discharge.4 In the year following implementation of PROTECT, the rate of appropriate prescribing of antithrombotics was 98%. Appropriate prescribing of angiotensin‐converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), statins, and thiazide diuretics was significantly increased from pre‐PROTECT levels.4 After 3 months of follow‐up, patient adherence to therapy remained high.5 The final results of the PROTECT program are not yet available; however, it is reasonable to expect that increased use of evidence‐based therapy and good patient adherence to these proven therapies will have led to better patient outcomes, including lower rates of recurrent stroke.

Patient outcomes data are available for a related initiative for treatment of patients hospitalized with myocardial infarction. Compared with the year prior to implementation of the Cardiac Hospitalization Atherosclerotic Management Program (CHAMP), more patients who were involved in the CHAMP intervention achieved low‐density lipoprotein cholesterol levels P < .001). In addition, these patients achieved a 57% reduction in recurrent myocardial infarction.6

These 2 studies indicate a benefit of establishing hospital‐based stroke systems; however, these studies are the initial steps, and each has limitations. For example, neither study was a prospective, randomized trial with a concurrent control group.4, 6 In addition, PROTECT data were not evaluated by independent audit but by individuals who were aware of the program goals, and limited data were available regarding contraindications to therapy.4 CHAMP did not assess adherence to nonpharmacologic interventions or the effect of surgical interventions.6 Large, randomized, controlled trials are needed to better understand the impact of such systems. Although larger evidence‐based trials are needed, it is important to review available information on stroke systems to adapt those components that align with each institution's available resources.

ESTABLISHING HOSPITAL‐BASED STROKE SYSTEMS

Several barriers exist to establishing a stroke systems care program, as detailed in Table 2. The support and involvement of the hospital administration is essential to success, as is multidisciplinary agreement that such a program will benefit patients.

Other potential points of resistance revolve around the financial impact of implementing a stroke systems approach to care. The proposed stroke systems care plan is consistent with meeting nationally recognized quality improvement standards; however, the current health care market forces demand accountability for health care expenditures. Increasingly, payers are turning to the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) and the National Committee for Quality Assurance (NCQA) evaluations to determine quality of care at various institutions. These programs encourage the use of standardized treatment protocols consistent with the concept of systems approach to care. Moreover, stroke care is a JCAHO quality measure and thus may have a financial impact on hospitals. It is possible that implementing standardized procedures for stroke care may reduce the cost of care. Information about the JCAHO Disease Specific Certification for Acute Stroke Care can be accessed at http://www.jointcommission.org/.7

Once there is agreement that a stroke system should be developed, a multidisciplinary team should be established. A multidisciplinary team may include hospitalists, neurologists, neurosurgeons, emergency medicine physicians, diagnostic and interventional radiologists, nurses, physiotherapists, occupational therapists, speech and language therapists, and social workers. However, the components of the multidisciplinary team may vary depending on the available staff and financial resources at different stroke centers. Assuring all participants in the system that their input is valued can improve communication among stroke specialists, hospitalists, and primary care clinicians. This team is responsible for evaluation of current procedures and development of algorithms, discharge forms, patient education, and preprinted orders.

The task of developing a cohesive plan for stroke care may appear onerous. Existing diagnostic and treatment procedures may be poorly designed or organized. However, multiple online sources provide tools for every aspect of stroke systems care. Information about evidence‐based stroke care practices is available as part of the American Heart Association (AHA)/ASA Get with the GuidelinesStroke program and can be accessed at http://www.strokeassociation.org.8 Standardized admission orders, patient education materials, and data‐monitoring methods are available at this site. Hospitalist‐specific information may also be found in the Stroke Resource Room of the Society of Hospital Medicine Web site (http://www.hospitalmedicine.org).9 A similar array of tools can be found at the PROTECT Web site (http://strokeprotect.mednet.ucla.edu).10 These materials are designed to facilitate integration of secondary prevention practices into stroke systems care.

A stroke system of care is a dynamic process. The multidisciplinary team may also be responsible for continuous monitoring and reporting of the efficiency and impact of the system and providing feedback to other staff and administration. Protocols should be revised regularly to account for new evidence‐based treatments and to streamline their use. The Canadian Stroke Systems Coalition recommends that a comprehensive and efficient system include prevention, prehospital and emergency care, hospital care, rehabilitation, reintegration into the community, surveillance, and research.11 Hospital staff should be educated in core competencies in hospital medicine as well as any changes to protocols made over time. Protocols that facilitate communication among health care providers should also be developed, and hospitalists may play a central role in this process. Accurate and timely transfer of patient information from the emergency department to the stroke center or ward is imperative.

FOCUSING ON INPATIENT CARE

Clinical pathways for inpatient care should be designed to limit stroke progression as much as possible.3 The Brain Attack Coalition (BAC) provides a resource for clinical pathways implemented at various institutes in the United States, including the Stanford Stroke Center, the Cleveland Clinic Foundation, and Thomas Jefferson University Hospital, among others (http://stroke‐site.org/pathways/pathways.html).12 Between 30% and 40% of acute stroke patients will show signs of stroke progression in the first week following stroke onset. Stroke can affect multiple systems, and symptom progression as a result of cerebral edema, hemorrhagic conversion, or additional strokes may require surgical intervention and warrants consultation with a neurologist.13

A neurologist should be available to the stroke system patients at all times, and ideally, all acute stroke patients should be evaluated by a neurologist specializing in the evaluation and treatment of patients with stroke.14 There are several stroke scales available to evaluate stroke patients, including the Barthel Index, the Glasgow outcome scale, the Modified Rankin Scale, the National Institutes of Health Stroke Scale, and the Hunt and Hess Classification of Subarachnoid Hemorrhage (http:// www.stroke‐site.org/stroke_scales/stroke_scales. html).15 These scales aid in the assessment of severity of stroke and may be helpful for hospitalists and other health care providers to recognize when a neurology consult is needed. The team should agree on criteria that indicate a neurological emergency, such as stroke progression, and other reasons for immediate consultation with a neurologist, such as worsening of stroke, stroke in a young patient, or uncertain diagnosis. These criteria should be included as an established part of the clinical pathway.

Common complications of stroke, such as myocardial infarction, deep vein thrombosis, pulmonary embolism, urinary tract infections, aspiration pneumonia, dehydration, poor nutrition, skin breakdown, and metabolic disorders, should be anticipated, and preventive steps should be taken. The measures to prevent the above complications of stroke need to be initiated in the emergency department.3

Management of existing comorbid conditions is another key part of subacute stroke care. Given that 85% of all hospitalists have a background in internal medicine, management of comorbid conditions such as diabetes and hypertension is an area in which hospitalists have professional competence. Patient history and use of prescription medications prior to stroke should be reviewed whenever possible and incorporated into short‐term and long‐term treatment plans. Patients with diabetes in particular may benefit more from rigorous control of blood pressure and lipids compared with other patients.16

Secondary stroke prevention should start as early as considered safe. Diagnosis of stroke subtype, often accomplished in the emergency department, establishes suitability for antithrombotics and optimal management strategy. Patients who receive a diagnosis of stroke secondary to cardioembolic atrial fibrillation should be treated with an anticoagulant after the acute period. Aspirin can be used for those individuals unable to use anticoagulants.16 For those individuals with stroke of noncardioembolic origin, particularly those with atherosclerosis and lacunar or cryptogenic infarcts, antiplatelet agents are recommended.14

A multimodal prevention strategy is recommended to manage blood pressure and dyslipidemia poststroke. An algorithm for managing blood pressure soon after stroke has been developed by the PROTECT program (Fig. 2).10 Antihypertensives, usually a combination of an ACE inhibitor and a thiazide diuretic, can be initiated at low doses 48‐72 hours after stroke. A longer delay is recommended for patients with large infarcts or evidence of uncontrolled hypertension. ARBs may be substituted for ACE inhibitors.10 Target blood pressures should be determined using the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.17 In general, even a reduction of 10/5 mm Hg has been shown to be beneficial.16

Figure 2

Statins are recommended for all patients with elevated serum lipids unless treatment with statins is contraindicated. The recommended target level for low‐density lipoprotein cholesterol is below 100 mg/dL for individuals with coronary heart disease and symptomatic atherosclerosis. A target below 70 mg/dL may be appropriate for patients at very high risk.16

Prior to discharge, patients or their caregivers should be given prescriptions adequate to cover the time until postdischarge follow‐up visit. The responsible persons need to be made aware that some medications such as antihypertensives will require dosage adjustments by an outpatient physician, and the timing of the follow‐up visit may need to be arranged accordingly.

The importance of stroke risk reduction should be part of predischarge patient education, along with a list of the warning signs of stroke. Adherence to the treatment regimen, including lifestyle changes and medications, should be emphasized. Patients or their caregivers should be educated about identifying adverse events and a plan to address them. Understanding that some adverse effects (eg, headache with aspirin plus extended‐release dipyridamole) are likely to be transient may prevent unnecessary discontinuation of treatment and reduce anxiety.

Patient and caregiver education can be reinforced by providing standardized patient education materials that can be found in the Stroke Resource Room at the Society of Hospital Medicine Web site (http://www.hospitalmedicine.org),9 PROTECT (http://strokeprotect.mednet.ucla.edu),10 ASA (http://www.strokeassociation.org),8 and AHA (http://www.americanheart.org)18 Web sites.

Transfer of patient information to outpatient health care providers is a critical step in stroke systems care. Notes indicating any need for medication dose adjustment must be included. Discharge summaries should be available to primary care providers, neurologists, and rehabilitation specialists prior to follow‐up visits. The use of electronic forms that can be faxed or sent by E‐mail can shorten delivery time considerably. In lieu of electronic delivery, physician letters can be used, and prototypes are available at the resource Web sites. Whenever possible, a follow‐up phone call to the primary care physician provides the best means to ensure clear communication.

SUMMARY

Hospitalists are well qualified to lead quality focused patient care initiatives at their institutions. Use of standardized protocols to reduce the risk of secondary stroke is proven to increase appropriate prescribing at discharge, which in turn improves patient adherence to evidence‐based therapy. Multidisciplinary communication, including communication with outpatient clinicians, facilitates the transition from inpatient to outpatient health care providers.

In addition to improving patient care, use of standardized protocols is tracked by JCAHO and offers assurance to payers that a particular hospital and its staff are committed to quality care. Establishing protocols is made relatively easy by the online availability of materials that can be adapted to various hospital settings.

Despite the considerable national attention drawn to the need for improved secondary stroke prevention, a gap remains between evidence and application for stroke and other vascular events. Experience with the Coverdell stroke registry has shown that a minority of acute stroke patients receive the care recommended in established guidelines.1 Data collected from 4 registry centers in the United States showed a consistent lack of appropriate diagnostics, patient education, and initiation of drug therapies proven to reduce the risk of recurrent stroke.1

According to a report from the Committee on the Quality of Healthcare in America published in 2001, suboptimal treatment as well as inefficient use of health resources can be largely attributed to fragmentation of health care delivery in the management of various diseases in the United States.2 In response to these findings, the American Stroke Association (ASA) has established recommendations for the development of stroke systems of care. The objective of a systems approach is to integrate preventive and treatment services and provide patients with evidence‐based care.3

During hospitalization for acute stroke, immediate treatment must focus on minimizing stroke progression, avoiding common complications, and preventing recurrent stroke. Prior to discharge, patients need to be educated about the importance of lifestyle modifications and pharmacotherapies to reduce their risk of a recurrence of the stroke and other atherosclerotic vascular events.3 As the physicians who focus on inpatient care, hospitalists are likely to be responsible for participating in and coordinating the multidisciplinary team that provides treatment and services to stroke patients. Hospitalists also must facilitate the transition from inpatient to outpatient care. Hospitalists are in a position to help educate stroke patients about prevention strategies throughout the hospitalization period. These functions provide hospitalists with the opportunity to lead, coordinate, and participate in stroke systems care at their institutions.

The present article discusses the components of stroke systems care recommended by the ASA and the best‐practices recommendations from the recent hospitalist roundtable discussion on routine acute stroke care. The national treatment guidelines and clinical trials supporting the recommendations of the hospitalist roundtable participants have been discussed in the article in this supplement by Dr. Likosky et al, as well as in the patient scenarios article in this supplement by Dr. Lee et al. Some of the anticipated barriers and pitfalls that may be encountered, along with potential solutions, are also discussed. Hospitalists may be able to use this review to adapt feasible components of the systems care for stroke management to improve care at their institutions.

WHAT IS STROKE SYSTEMS CARE?

A stroke system is coordinated stroke care along the entire continuum from primary prevention to rehabilitation. Postemergency department inpatient care for patients with acute stroke, also referred to as subacute care, is only one component of the community‐based stroke systems of care recommended by the ASA (Fig. 1).3 In this model, regional stroke systems identify hospitals that are acute stroke capable and determine that those institutions use clinical pathways that reflect well‐established standards of care and nationally recognized guidelines.3 In this broad sense of the term, stroke systems function to organize and coordinate the various agencies and health care providers responsible for caring for patients with stroke, from the first call to emergency services through postdischarge medical care and rehabilitation (Table 1). The subacute phase of care provides the bridge from management of the medical emergency to discharge and is central to secondary stroke prevention.

Figure 1

RATIONALE FOR HOSPITAL‐BASED STROKE SYSTEMS

The Preventing Recurrence of Thrombo‐embolic Events through Coordinated Treatment (PROTECT) program provides proof of concept.4 The PROTECT program was implemented at a large teaching hospital to improve diagnosis, treatment, and secondary prevention for patients with ischemic stroke.4 Four medication goals and instruction in 4 lifestyle interventions were chosen as indicators of program impact. In the first year after PROTECT was started, 100% of eligible patients received instruction in all 4 areas of lifestyle change prior to discharge.4 In the year following implementation of PROTECT, the rate of appropriate prescribing of antithrombotics was 98%. Appropriate prescribing of angiotensin‐converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), statins, and thiazide diuretics was significantly increased from pre‐PROTECT levels.4 After 3 months of follow‐up, patient adherence to therapy remained high.5 The final results of the PROTECT program are not yet available; however, it is reasonable to expect that increased use of evidence‐based therapy and good patient adherence to these proven therapies will have led to better patient outcomes, including lower rates of recurrent stroke.

Patient outcomes data are available for a related initiative for treatment of patients hospitalized with myocardial infarction. Compared with the year prior to implementation of the Cardiac Hospitalization Atherosclerotic Management Program (CHAMP), more patients who were involved in the CHAMP intervention achieved low‐density lipoprotein cholesterol levels P < .001). In addition, these patients achieved a 57% reduction in recurrent myocardial infarction.6

These 2 studies indicate a benefit of establishing hospital‐based stroke systems; however, these studies are the initial steps, and each has limitations. For example, neither study was a prospective, randomized trial with a concurrent control group.4, 6 In addition, PROTECT data were not evaluated by independent audit but by individuals who were aware of the program goals, and limited data were available regarding contraindications to therapy.4 CHAMP did not assess adherence to nonpharmacologic interventions or the effect of surgical interventions.6 Large, randomized, controlled trials are needed to better understand the impact of such systems. Although larger evidence‐based trials are needed, it is important to review available information on stroke systems to adapt those components that align with each institution's available resources.

ESTABLISHING HOSPITAL‐BASED STROKE SYSTEMS

Several barriers exist to establishing a stroke systems care program, as detailed in Table 2. The support and involvement of the hospital administration is essential to success, as is multidisciplinary agreement that such a program will benefit patients.

Other potential points of resistance revolve around the financial impact of implementing a stroke systems approach to care. The proposed stroke systems care plan is consistent with meeting nationally recognized quality improvement standards; however, the current health care market forces demand accountability for health care expenditures. Increasingly, payers are turning to the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) and the National Committee for Quality Assurance (NCQA) evaluations to determine quality of care at various institutions. These programs encourage the use of standardized treatment protocols consistent with the concept of systems approach to care. Moreover, stroke care is a JCAHO quality measure and thus may have a financial impact on hospitals. It is possible that implementing standardized procedures for stroke care may reduce the cost of care. Information about the JCAHO Disease Specific Certification for Acute Stroke Care can be accessed at http://www.jointcommission.org/.7

Once there is agreement that a stroke system should be developed, a multidisciplinary team should be established. A multidisciplinary team may include hospitalists, neurologists, neurosurgeons, emergency medicine physicians, diagnostic and interventional radiologists, nurses, physiotherapists, occupational therapists, speech and language therapists, and social workers. However, the components of the multidisciplinary team may vary depending on the available staff and financial resources at different stroke centers. Assuring all participants in the system that their input is valued can improve communication among stroke specialists, hospitalists, and primary care clinicians. This team is responsible for evaluation of current procedures and development of algorithms, discharge forms, patient education, and preprinted orders.

The task of developing a cohesive plan for stroke care may appear onerous. Existing diagnostic and treatment procedures may be poorly designed or organized. However, multiple online sources provide tools for every aspect of stroke systems care. Information about evidence‐based stroke care practices is available as part of the American Heart Association (AHA)/ASA Get with the GuidelinesStroke program and can be accessed at http://www.strokeassociation.org.8 Standardized admission orders, patient education materials, and data‐monitoring methods are available at this site. Hospitalist‐specific information may also be found in the Stroke Resource Room of the Society of Hospital Medicine Web site (http://www.hospitalmedicine.org).9 A similar array of tools can be found at the PROTECT Web site (http://strokeprotect.mednet.ucla.edu).10 These materials are designed to facilitate integration of secondary prevention practices into stroke systems care.

A stroke system of care is a dynamic process. The multidisciplinary team may also be responsible for continuous monitoring and reporting of the efficiency and impact of the system and providing feedback to other staff and administration. Protocols should be revised regularly to account for new evidence‐based treatments and to streamline their use. The Canadian Stroke Systems Coalition recommends that a comprehensive and efficient system include prevention, prehospital and emergency care, hospital care, rehabilitation, reintegration into the community, surveillance, and research.11 Hospital staff should be educated in core competencies in hospital medicine as well as any changes to protocols made over time. Protocols that facilitate communication among health care providers should also be developed, and hospitalists may play a central role in this process. Accurate and timely transfer of patient information from the emergency department to the stroke center or ward is imperative.

FOCUSING ON INPATIENT CARE

Clinical pathways for inpatient care should be designed to limit stroke progression as much as possible.3 The Brain Attack Coalition (BAC) provides a resource for clinical pathways implemented at various institutes in the United States, including the Stanford Stroke Center, the Cleveland Clinic Foundation, and Thomas Jefferson University Hospital, among others (http://stroke‐site.org/pathways/pathways.html).12 Between 30% and 40% of acute stroke patients will show signs of stroke progression in the first week following stroke onset. Stroke can affect multiple systems, and symptom progression as a result of cerebral edema, hemorrhagic conversion, or additional strokes may require surgical intervention and warrants consultation with a neurologist.13

A neurologist should be available to the stroke system patients at all times, and ideally, all acute stroke patients should be evaluated by a neurologist specializing in the evaluation and treatment of patients with stroke.14 There are several stroke scales available to evaluate stroke patients, including the Barthel Index, the Glasgow outcome scale, the Modified Rankin Scale, the National Institutes of Health Stroke Scale, and the Hunt and Hess Classification of Subarachnoid Hemorrhage (http:// www.stroke‐site.org/stroke_scales/stroke_scales. html).15 These scales aid in the assessment of severity of stroke and may be helpful for hospitalists and other health care providers to recognize when a neurology consult is needed. The team should agree on criteria that indicate a neurological emergency, such as stroke progression, and other reasons for immediate consultation with a neurologist, such as worsening of stroke, stroke in a young patient, or uncertain diagnosis. These criteria should be included as an established part of the clinical pathway.

Common complications of stroke, such as myocardial infarction, deep vein thrombosis, pulmonary embolism, urinary tract infections, aspiration pneumonia, dehydration, poor nutrition, skin breakdown, and metabolic disorders, should be anticipated, and preventive steps should be taken. The measures to prevent the above complications of stroke need to be initiated in the emergency department.3

Management of existing comorbid conditions is another key part of subacute stroke care. Given that 85% of all hospitalists have a background in internal medicine, management of comorbid conditions such as diabetes and hypertension is an area in which hospitalists have professional competence. Patient history and use of prescription medications prior to stroke should be reviewed whenever possible and incorporated into short‐term and long‐term treatment plans. Patients with diabetes in particular may benefit more from rigorous control of blood pressure and lipids compared with other patients.16

Secondary stroke prevention should start as early as considered safe. Diagnosis of stroke subtype, often accomplished in the emergency department, establishes suitability for antithrombotics and optimal management strategy. Patients who receive a diagnosis of stroke secondary to cardioembolic atrial fibrillation should be treated with an anticoagulant after the acute period. Aspirin can be used for those individuals unable to use anticoagulants.16 For those individuals with stroke of noncardioembolic origin, particularly those with atherosclerosis and lacunar or cryptogenic infarcts, antiplatelet agents are recommended.14

A multimodal prevention strategy is recommended to manage blood pressure and dyslipidemia poststroke. An algorithm for managing blood pressure soon after stroke has been developed by the PROTECT program (Fig. 2).10 Antihypertensives, usually a combination of an ACE inhibitor and a thiazide diuretic, can be initiated at low doses 48‐72 hours after stroke. A longer delay is recommended for patients with large infarcts or evidence of uncontrolled hypertension. ARBs may be substituted for ACE inhibitors.10 Target blood pressures should be determined using the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.17 In general, even a reduction of 10/5 mm Hg has been shown to be beneficial.16

Figure 2

Statins are recommended for all patients with elevated serum lipids unless treatment with statins is contraindicated. The recommended target level for low‐density lipoprotein cholesterol is below 100 mg/dL for individuals with coronary heart disease and symptomatic atherosclerosis. A target below 70 mg/dL may be appropriate for patients at very high risk.16

Prior to discharge, patients or their caregivers should be given prescriptions adequate to cover the time until postdischarge follow‐up visit. The responsible persons need to be made aware that some medications such as antihypertensives will require dosage adjustments by an outpatient physician, and the timing of the follow‐up visit may need to be arranged accordingly.

The importance of stroke risk reduction should be part of predischarge patient education, along with a list of the warning signs of stroke. Adherence to the treatment regimen, including lifestyle changes and medications, should be emphasized. Patients or their caregivers should be educated about identifying adverse events and a plan to address them. Understanding that some adverse effects (eg, headache with aspirin plus extended‐release dipyridamole) are likely to be transient may prevent unnecessary discontinuation of treatment and reduce anxiety.

Patient and caregiver education can be reinforced by providing standardized patient education materials that can be found in the Stroke Resource Room at the Society of Hospital Medicine Web site (http://www.hospitalmedicine.org),9 PROTECT (http://strokeprotect.mednet.ucla.edu),10 ASA (http://www.strokeassociation.org),8 and AHA (http://www.americanheart.org)18 Web sites.

Transfer of patient information to outpatient health care providers is a critical step in stroke systems care. Notes indicating any need for medication dose adjustment must be included. Discharge summaries should be available to primary care providers, neurologists, and rehabilitation specialists prior to follow‐up visits. The use of electronic forms that can be faxed or sent by E‐mail can shorten delivery time considerably. In lieu of electronic delivery, physician letters can be used, and prototypes are available at the resource Web sites. Whenever possible, a follow‐up phone call to the primary care physician provides the best means to ensure clear communication.

SUMMARY

Hospitalists are well qualified to lead quality focused patient care initiatives at their institutions. Use of standardized protocols to reduce the risk of secondary stroke is proven to increase appropriate prescribing at discharge, which in turn improves patient adherence to evidence‐based therapy. Multidisciplinary communication, including communication with outpatient clinicians, facilitates the transition from inpatient to outpatient health care providers.

In addition to improving patient care, use of standardized protocols is tracked by JCAHO and offers assurance to payers that a particular hospital and its staff are committed to quality care. Establishing protocols is made relatively easy by the online availability of materials that can be adapted to various hospital settings.

The risk of recurrent stroke is high following an ischemic stroke or transient ischemic attack (TIA).16 Within the first 90 days following an initial TIA, between 4.8% and 18.3% of individuals will have an ischemic stroke, with many experiencing an ischemic event within the first 27 days.14 The risk of subsequent stroke in a stroke survivor is high as well4.2% at 6 months, 6.5% at 1 year, and 11.8% at 3 years.5 The management of these patients poses substantial challenges for the health care professional. Prevention of secondary stroke, with its risk for greater morbidity and mortality, is a priority. However, depending on the cause of the event, patient comorbidities, and other factors, the most effective therapeutic strategies may differ. For example, cardioembolic strokes, which constitute approximately 20% of ischemic strokes, are treated with anticoagulants, whereas strokes of noncardioembolic origin are usually treated with antiplatelet agents.7, 8 Other risk factors or variables such as recent stent placement or reduced left ventricular ejection fraction (LVEF) may affect therapeutic decisions as well, although in many cases clear data are not available to direct these difficult decisions. Thus, although antiplatelet agents, including aspirin, clopidogrel, and aspirin plus extended‐release dipyridamole, prevent strokes, the choice of agent depends on the individual patient risk profile. A number of challenging patient scenarios are explored in this article with the goal of providing a context for some of the more recent trial data.

RECENT STENT PLACEMENT

In 2004, there were approximately 663,000 percutaneous coronary interventions (PCIs).9 Stenting after PCI is a common procedure and is used in more than 70% of coronary angioplasty procedures. The addition of stenting to the PCI procedure has improved the outcome for patients, reducing the need for revascularization.10 Because restenosis of the area following stent placement is common, drug‐eluting stents are also used to allow slow release of antiproliferative agents such as sirolimus or paclitaxel.11, 12

Studies such as Percutaneous Coronary InterventionClopidogrel in Unstable Angina to Prevent Recurrent Events (PCI‐CURE) and Clopidogrel for Reduction of Events During Observation (CREDO) have supported the use of up to 8 months of clopidogrel plus aspirin following coronary interventions.13, 14 The European Society of Cardiology PCI guidelines state that in regard to PCI procedures, clopidogrel is superior to aspirin. The guidelines recommend 34 weeks of clopidogrel following stenting in patients with stable angina but up to 12 months in patients receiving brachytherapy. Among patients who have received drug‐eluting stents, clopidogrel therapy should be continued for 612 months. In contrast, aspirin therapy (75100 mg/day) should be continued for life in all these patients.10 In patients who have had a nonST segment elevation myocardial infarction (MI) or who have unstable angina, these guidelines recommend the continuation of clopidogrel (75 mg/day) plus aspirin (100 mg/day) for 912 months after a PCI procedure.10

However, although clopidogrel plus aspirin reduces the incidence of major ischemic events in the period immediately following a stenting procedure, some have suggested that long‐term use of clopidogrel is not supported by the evidence.14 It has been proposed that the sustained beneficial effect of clopidogrel given in the immediate postoperative period may account for much of the long‐term benefit, as has been shown to be true of the glycoprotein IIb/IIIa antagonists.14 However, others caution that in the case of drug‐eluting stents, inhibition of endothelialization of the stent struts by the embedded agents makes these stents more susceptible to thrombosis formation, particularly if therapy with clopidogrel plus aspirin is interrupted.12 It is believed that late stent thrombosis, which has a high mortality rate, is more common with drug‐eluting stents than with bare‐metal stents.12, 15 As a result, many cardiologists recommend at least 12 months of dual antiplatelet therapy with aspirin plus clopidogrel for patients who have received drug‐eluting stents.12 However, given the results of the recent Management of Atherothrombosis in High‐risk Patients with Recent Transient Ischemic Attack or Ischemic Stroke (MATCH) and Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trials,16, 17 in particular, the high incidence of bleeding events in the clopidogrel plus aspirin group, there are concerns about longer‐term or lifelong therapy with this combination in a population at risk for recurrent stroke.

What about the patient who has undergone a coronary stent placement in the past 12 months and experiences a subsequent ischemic stroke or TIA? The patient should be continued on clopidogrel plus aspirin for the recommended time, as premature discontinuation of antiplatelet therapy increases the risk of stent thrombosis.18 No data are currently available to support decision making regarding these patients. However, it has been suggested that among patients given drug‐eluting stents, extended use of clopidogrel at 6, 12, and 24 months is associated with reduced risk of death or death/MI.18

LOW EJECTION FRACTION

Patients who have had a stroke or TIA and have underlying left ventricular dysfunction are at increased risk of a cardioembolic stroke.8 The reduction in stroke volume creates a condition of stasis in the ventricle that increases the likelihood of coagulation and thromboembolic events.8, 19 Evidence indicates that the risk of stroke is inversely correlated with LVEF; LVEF of 29%35% carries a cumulative 5‐year stroke risk of 7.8%, and LVEF of 28% or below carries a 5‐year risk of 8.9%.8, 20, 21 Data from the Survival and Ventricular Enlargement (SAVE) study showed an 18% increase in the risk of stroke for every 5% decline in LVEF,19, 21 and the Studies of Left Ventricular Dysfunction (SOLVD) trial found a 58% increase in thromboembolic events for every 10% decrease in LVEF among women (P = .01).19, 22 Among patients with low LVEF who have had a stroke, the 5‐year recurrent stroke rate may be as high as 45%.19, 23

Although it would appear that stroke associated with left ventricular dysfunction and a low LVEF may potentially be cardioembolic in origin, risk reduction for recurrent stroke has not been adequately investigated as a primary end point in clinical trials, particularly in the absence of atrial fibrillation.24 Thus, the question of whether antiplatelet or anticoagulant therapy would be more effective has not yet been answered. However, results of secondary end point analyses in the SOLVD and SAVE trials suggested that patients had a lower risk of sudden death, thromboembolism, and stroke with antiplatelet therapy.21, 2426 In an observational analysis of prospectively collected data on patients enrolled in the SAVE trial, use of aspirin reduced the overall risk of stroke by 66% in patients with an LVEF below 28%.21 Warfarin is the standard of care for stroke prevention in atrial fibrillation, and the 2 conditions often coexist. In those patients, warfarin is the recommended therapy.24

In patients with sinus rhythm and a low LVEF, the choice is less clear. The results of the Warfarin/Aspirin Study in Heart failure (WASH) failed to establish efficacy or safety for aspirin in preventing all‐cause mortality, nonfatal MI, and nonfatal stroke in patients with heart failure. Patients treated with aspirin were significantly more likely to be hospitalized for cardiovascular events, especially worsening heart failure.27 The trial found no significant difference for the composite end point between the 3 treatment groups: aspirin, warfarin, or no antithrombotic treatment. However, this was a small trial, and the findings were far from definitive, as the study was designed primarily to be a feasibility study to aid in the design of a larger outcomes study.24 Because of the inconsistent results and lack of well‐designed studies regarding the benefit of aspirin or anticoagulation for secondary stroke prevention in patients with LVEF in the absence of atrial fibrillation, further study is needed.

More recently, results were presented from the Warfarin and Antiplatelet Therapy in Heart Failure Trial (WATCH), which randomized patients with heart failure, sinus rhythm, and LVEF of 35% or below to either aspirin 162 mg, warfarin (target international normalized ratio [INR] 2.53.0), or clopidogrel.28, 29 Two major comparisons were plannedwarfarin versus aspirin and aspirin versus clopidogrel.28 Whereas warfarin therapy was open‐label because of the need to check blood levels, antiplatelet therapy was given in a double‐blind manner. After a mean follow‐up of 23 months, no significant differences were found for the primary composite end point of all‐cause mortality, nonfatal MI, and nonfatal stroke, which occurred in 20.5% of those on aspirin, 19.8% on warfarin, and 21.8% on clopidogrel. However, for the secondary end point of stroke, there was a strong trend favoring warfarin over aspirin: stroke occurred in 0.7% of patients taking warfarin versus 2.1% of those taking aspirin (P = .06).24, 29 However, the WATCH investigators concluded that the question of warfarin's value for patients with low LVEF and sinus rhythm remained unresolved.29

In the absence of clear data, the American Heart Association (AHA)/American Stroke Association (ASA) guidelines on stroke prevention in this patient population recommend either warfarin (INR 2.03.0) or antiplatelet therapy, including aspirin (50325 mg/day), aspirin plus extended‐release dipyridamole (200 mg twice daily), or clopidogrel (75 mg/day).8 Patients with coexisting atrial fibrillation should be treated with warfarin, or if unable to tolerate that agent, aspirin 325 mg/day.8

The Warfarin Versus Aspirin for Reduced Cardiac Ejection Fraction (WARCEF) trial may provide more definitive answers on the best approach for reducing the risk of recurrent stroke in patients with low LVEF. The study will compare warfarin (INR 2.53.0) and aspirin (325 mg/day) in the prevention of all‐cause mortality and all strokes (ischemic and hemorrhagic) in patients with an LVEF of 35% or below but no atrial fibrillation.30 The study has a target enrollment of 2860 patients, who are being recruited at 70 North American and 70 European sites, and it will include patients with recent stroke or TIA.28 The results are anxiously anticipated.

INTRACRANIAL STENOSIS

Stroke patients with symptomatic intracranial atherosclerosis have a high risk of recurrent strokein the range of 10% per yearand this accounts for approximately 8% of ischemic strokes.8, 31, 32 Intracranial stenosis appears to be more common in African Americans and Hispanics than in white patients.31

Recurrent stroke prevention in patients with intracranial stenosis was explored in the Warfarin‐Aspirin Symptomatic Intracranial Disease (WASID) study, a multicenter, double‐blind trial. Patients with angiographically verified 50%99% stenosis of a major intracranial artery who had experienced either a stroke or TIA were randomized to either warfarin (target INR 2.03.0) or high‐dose aspirin (1300 mg/day). The primary end point was ischemic stroke, brain hemorrhage, or death from vascular causes other than stroke.33 Mean follow‐up was 1.8 years, and enrollment was stopped after 569 patients had been randomized because of concerns about the safety of warfarin in this patient population.33 The primary end point occurred in 22.1% of those treated with aspirin and 21.8% of those treated with warfarin.33 There were no significant differences between the 2 treatment groups for any of the prespecified secondary end points, including ischemic stroke in any vascular territory and ischemic stroke in the territory of the stenotic intracranial artery.33

The rate of death was significantly higher in the warfarin group (9.7%) than in the aspirin group (4.3%; P = .02). Patients in the warfarin group had higher rates of death from both vascular and nonvascular causes.33 Major hemorrhage was significantly more common in the warfarin group (8.3%) than in the aspirin group (3.2%; P = .01). The investigators concluded that warfarin should not be used as first‐line prevention of recurrent stroke in patients with intracranial stenosis. However, there was a significant association between an INR less than 2 and increased risk of ischemic stroke and major cardiac events (P < .001) as well as a significant increase in major hemorrhages in patients with INRs greater than 3 (P < .001).33

The failure of many patients in the study to remain within the therapeutic INR casts doubt on these results to some extent, although this may actually mirror a common real‐world scenario. Patients were within the therapeutic INR goal only 63% of the time. Furthermore, a nonstandard high dose of aspirin (1300 mg/day) was used, which also may have affected the results.34 Others looking at this data have suggested that aspirin remains an imperfect therapy, with an unacceptably high risk of ischemic stroke and other vascular events, and that anticoagulation may play a role in the period immediately following ischemic stroke or TIA with transition to antiplatelet therapy.34 This would require additional investigation.34

The current AHA/ASA guidelines recommend that for patients with noncardioembolic ischemic stroke or TIA, antiplatelet agents rather than oral anticoagulants be used to reduce the risk of recurrent stroke (class I, level A). Aspirin (50325 mg/day), the combination of aspirin and extended‐release dipyridamole, and clopidogrel are all acceptable options for initial therapy (class IIa, level A).8 The combination of aspirin and extended‐release dipyridamole is suggested instead of aspirin alone (class IIa, level A), and clopidogrel may be considered instead of aspirin alone (class IIb, level B).8 However, data are insufficient at this point to make evidence‐based recommendations between antiplatelet options other than aspirin.8 In patients with significant intracranial stenosis whose symptoms persist despite medical therapy, including antithrombotics, statins, and antihypertensives, endovascular therapy with angioplasty and/or stent placement is an option, but it remains investigational and its value is uncertain.8

CAROTID STENOSIS

Asymptomatic carotid stenosis greater than 50% has been found in 7% of men and 5% of women older than 65 years.35, 36 Among those with asymptomatic carotid stenosis greater than 50%, there is an annual risk of stroke of up to 3.4%.35 In such patients, the benefit of carotid endarterectomy (CEA) is highly dependent on the surgical risk, and if complication rates exceed 3.0%, benefit is eliminated.35 The AHA/ASA guidelines recommend that patients be given treatment for all identifiable risk factors, including statins for dyslipidemia, antihypertensives for hypertension, and aspirin as an antiplatelet agent. In select patients with high‐grade asymptomatic carotid stenosis, CEA performed by a surgeon with a morbidity/mortality rate below 3% is recommended.35 In asymptomatic patients with greater than 70% carotid stenosis, CEA can be an effective therapy. Trial data indicate that the overall 5‐year risk of any stroke or perioperative death is 11.8% for deferred surgery versus 6.4% for immediate endarterectomy (P < .0001).35, 37 Unfortunately, data on the value of stents or angioplasty compared with CEA in this patient population are limited.35

In patients who have had a recent TIA or stroke, carotid stenosis would be considered symptomatic. In these patients, the benefit of CEA is strongly associated with the degree of stenosis. Data from the Carotid Endarterectomy Trialists' Collaboration and North American Symptomatic Carotid Endarterectomy Trial (NASCET) have shown that in patients with stenosis greater than 70%, CEA reduces the absolute 5‐year risk of ischemic stroke by 16.0% (P < .001), whereas in patients with 50%69% stenosis, the 5‐year absolute risk reduction is 4.6% (P = .04). In those with stenosis of 30%49%, there is no effect, and CEA in patients with less than 30% stenosis increases the risk of stroke.38, 39 In patients with 50%69% stenosis, benefit is achieved only if patients at highest risk are selected.40 Recent data have also questioned the typical 4‐ to 6‐week delay before performing a CEA following a nondisabling stroke. Rothwell et al. found that surgery performed within 2 weeks of such a stroke was not associated with increased operative risk.41 Moreover, benefit from CEA fell rapidly within the first few weeks after a TIA or stroke, particularly in women, perhaps reflecting the high risk of recurrent stroke in the period immediately following an initial event.41

Angioplasty or stents have been investigated as alternatives to CEA, but the evidence to date has been disappointing. The Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) demonstrated preventive efficacy and major risks similar to those found for CEA after 3 years of follow‐up in 504 patients with carotid stenosis.42 However, a more recent study was stopped prematurely after 527 patients had been enrolled because of a higher incidence of disabling stroke or death at 30 days in the stenting cohort (3.4%) compared with the CEA cohort (1.5%). The 30‐day incidence of any stroke or death was 3.9% after CEA and 9.6% after stenting, yielding a relative risk of 2.5 for stenting.43 The Stent‐Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients (SPACE) trial has also failed to find benefit for carotid stenting and/or angioplasty in comparison with CEA.44

The AHA/ASA guidelines recommend CEA in patients with ipsilateral severe (70%99%) stenosis and a recent TIA or ischemic stroke (within 6 months). Surgery should be performed by a surgeon with a perioperative morbidity/mortality rate less than 6%.8 In patients with 50%69% stenosis, the advisability of CEA depends on patient factors such as age, sex, comorbidities, and severity of symptoms. Surgery should be performed within 2 weeks of an ischemic event. In patients with severe stenosis in whom CEA would be difficult to perform, carotid angioplasty or stenting may be recommended if performed by practitioners with a morbidity/mortality rate less than 4%6%.8 The Seventh ACCP Conference also recommends that patients undergoing CEA receive aspirin 81325 mg/day prior to and following the procedure.7

ATHEROSCLEROSIS OF THE AORTIC ARCH

Atherosclerosis of the aortic arch contributes significantly as an independent factor to risk of embolic stroke.7 Such plaques can be detected using transesophageal echocardiography; those that are thicker than 45 mm, exhibit ulceration, or have mobile components place individuals at higher risk for stroke.7, 45 The stroke risk associated with aortic arch plaques greater than 5 mm is as high as 33% per year.7, 46

However, data from large‐scale randomized clinical trials on the efficacy of therapeutic interventions in this condition are lacking. Two small trials found efficacy for warfarin in patients with mobile thrombi in the thoracic aorta. In one, patients given oral anticoagulants had better outcomes than those treated with antiplatelet agents, and in the other, warfarin proved to be more effective than no treatment.47, 48 A retrospective trial that looked at 519 patients treated with warfarin, antiplatelet agents, or statins found there was a protective effect of statins, with an absolute risk reduction in embolic events, including ischemic stroke, TIA, and peripheral embolization of 17%, and a relative risk reduction in embolic events of 59%. The odds ratio for embolic events was 0.39 for statins, 0.77 for antiplatelet agents, and 1.18 for warfarin.49 The French Study of Aortic Plaque in Stroke found no significant difference in risk of events between those treated with warfarin and those treated with aspirin; however, this study was not designed as a therapeutic trial, and few patients received warfarin, casting doubt on this finding.45

Given the paucity of data, suggestions for treatment of patients with an aortic arch atheromata are difficult. Certainly, statin therapy, which would address general atherosclerotic risk reduction, can be initiated. Warfarin appeared to be more effective than antiplatelet agents in several of the studies; however some have expressed concern about the possibility of anticoagulation increasing the risk of cholesterol embolism in these patients.7

SYMPTOMATIC CORONARY ARTERY DISEASE

For patients with a history of ischemic stroke or TIA who have symptomatic CAD, their condition must be managed for both stroke and CAD risks. In patients with stable or unstable angina and a history of stroke or TIA, similar risks must be managed. The acute treatment of ACS or symptomatic CAD cannot be adequately addressed here; however, it may involve a number of therapeutic modalities, including PCI, ‐blocker therapy, glycoprotein IIb/IIIa inhibitors, anticoagulant therapy, angiotensin‐converting enzyme (ACE) inhibitors, and clopidogrel plus aspirin, depending on the exact nature of the syndrome.5054 The long‐term management and, in particular, prevention of recurrent stroke in the setting of symptomatic CAD are the focus here. As with a patient with a history of CAD and a recent TIA or stroke (as discussed earlier), patients with symptomatic CAD and TIA or stroke must be managed for multiple risk factors. NCEP guidelines recommend aggressive cholesterol lowering with statin therapy. Hypertension must be addressed as well, and long‐term therapy with ‐blockers and ACE inhibitors has been shown to reduce mortality in patients with ACS and is recommended by the AHA/ASA.5355

Once the acute ACS period has resolved, it is reasonable to address the question of the best possible antiplatelet therapy for long‐term stroke prevention. Long‐term use of clopidogrel plus aspirin is not advisable given the increased risk of bleeding events noted in the MATCH and CHARISMA trials.16, 17 At this point, it would be reasonable to start the patient on aspirin 75150 mg/day, which reduces risk of stroke up to 25%,56, 57 aspirin plus extended‐release dipyridamole, which reduces risk by about 37%,57, 58 or clopidogrel 75 mg/day, which reduces the relative risk for stroke alone by 7.3% compared with aspirin.59 In patients who cannot tolerate or are allergic to aspirin, clopidogrel is a reasonable choice.8

ANTIPLATELET FAILURE

Patients who have failed antiplatelet therapythat is, have gone on to have a recurrent strokeare particularly difficult. It is important to remember that any therapeutic intervention only reduces stroke risk; it does not eliminate it. Keeping that in mind, it is essential to reevaluate and reconsider both the original diagnosis and the etiology of the stroke or TIA. A number of diagnostic alternatives should be considered, including sensory seizure and migraine equivalents, as well as other etiologies, such as atrial fibrillation or cerebral amyloid angiopathy. Therapy may have to be adjusted accordingly, but the patient remains at increased risk for stroke recurrence, and thus preventive therapy is critical.

Several key points should be remembered. As outlined previously in this article, if the stroke is still thought to be noncardioembolic in origin, a reduction in the risk of stroke has not been found for those patients receiving warfarin, an increased dose of aspirin, a combination of antiplatelet agents and warfarin, or clopidogrel plus aspirin.8, 16, 31, 60, 61 However, if atrial fibrillation has developed in the patient, the recommendation is warfarin (INR 2.03.0) or, if anticoagulants cannot be taken, aspirin 325 mg/day.8 Risk factors should be reassessed and managed, with agents and lifestyle changes to control hypertension and dyslipidemia. Antiplatelet agents should be continued in patients with noncardioembolic stroke. Acceptable antiplatelet agents include aspirin (50325 mg/day), aspirin plus extended‐release dipyridamole, and clopidogrel. The combination of aspirin plus extended‐release dipyridamole is suggested over aspirin alone. If the patient cannot tolerate or is allergic to aspirin, clopidogrel is a reasonable alternative.8 The decision of which antiplatelet agent to use should be based on the individual patient's risk factor profile.8 The temptation to put patients on anticoagulation therapy because of a wish to do more should be avoided, as this is likely to expose patients to increased risk without known benefit.60, 61

Consider a common case scenarioa patient with a known history of hypertension and TIA presents with a 30‐minute episode of left arm numbness. The patient has been adherent to his prescribed medications, including aspirin 81 mg/day. What is the appropriate approach to acute treatment at this time? This is a common scenario in emergency departmentsnew‐onset TIA while taking aspirin 81 mg/day. There are advocates for several different treatment regimens in these patients: increasing the aspirin dose to 325 mg/day as a new treatment; discontinuing aspirin and initiating clopidogrel 75 mg/day; discontinuing aspirin 81 mg/day and initiating aspirin 325 mg/day plus clopidogrel 75 mg/day; or discontinuing aspirin 81 mg/day and initiating a combination of aspirin 25 mg plus extended‐release dipyridamole 200 mg twice daily. It is clear that patients with the same disease are treated differently in different institutions. What is the appropriate evidence‐based treatment in this case? The answer is clearno evidence supports increasing the dose of aspirin as a new treatment for this case or initiating aspirin 325 mg/day plus clopidogrel 75 mg/day.16, 17 Based on the literature, for a patient who has recently had another cerebral ischemic event while on treatment, it would make sense to consider switching to another agent. Three agents are recommended by the guidelines: aspirin, clopidogrel, and aspirin plus extended‐release dipyridamole. If treatment 1 were to fail, it would not be against the evidence to initiate treatment 2 or 3.

PATIENTS ON WARFARIN

Data from the Warfarin‐Aspirin Recurrent Stroke Study (WARSS), a large‐scale recurrent stroke prevention trial conducted in 2206 patients, demonstrated that there was no survival benefit for noncardioembolic stroke survivors who were treated with warfarin.60, 61 Yet there are patients still taking warfarin to reduce stroke risk who do not have atrial fibrillation. Unless a patient is allergic to or intolerant of antiplatelet agents such as aspirin, clopidogrel, or dipyridamole, they should not be treated with warfarin for noncardioembolic stroke risk.8 The results of other studies of anticoagulation in recurrent stroke prevention, including the European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT),62 the Stroke Performance for Reporting the Improvement and Translation (SPIRIT) trial,63 and the WASID study,33 have yet to demonstrate a role for warfarin in prevention of noncardioembolic stroke.

Given these trial results, patients currently on warfarin who do not have a cardioembolic risk factor should be placed on antiplatelet therapy with aspirin, aspirin plus extended‐release dipyridamole, or clopidogrel 35 days after discontinuing warfarin therapy. However, it would be advisable to evaluate these patients for atrial fibrillation, as patients with that risk factor should remain on warfarin.8

SUMMARY

In clinical practice, health care providers often must manage patients with complex profiles. Multiple risk factors and comorbidities complicate treatment of these individuals, and robust clinical data are often lacking as clinical trials rarely include such individuals. Guidelines offer recommendations, but these too are often based on extrapolations from clinical trial data. This is particularly true of patients at risk for ischemic stroke, as the primary underlying causevascular diseasehas systemic implications and comorbidities that often complicate treatment.

In general, antiplatelet therapy should be used to prevent recurrent stroke in patients with TIA or noncardioembolic stroke, whereas anticoagulation therapy should be used in patients with cardioembolic stroke such as that caused by atrial fibrillation. However, therapy must be individualized to account for the patient's full risk profile. Conditions such as dyslipidemia and hypertension must be addressed as well, as these not only give rise to stroke but also to the CAD, coronary heart disease, and ACS that may coexist with stroke. Among patients deemed suitable for antiplatelet therapy, class IIa, level A evidence supports the use of aspirin 50325 mg/day, the combination of aspirin and extended‐release dipyridamole, and clopidogrel for secondary prevention of stroke.8

The risk of recurrent stroke is high following an ischemic stroke or transient ischemic attack (TIA).16 Within the first 90 days following an initial TIA, between 4.8% and 18.3% of individuals will have an ischemic stroke, with many experiencing an ischemic event within the first 27 days.14 The risk of subsequent stroke in a stroke survivor is high as well4.2% at 6 months, 6.5% at 1 year, and 11.8% at 3 years.5 The management of these patients poses substantial challenges for the health care professional. Prevention of secondary stroke, with its risk for greater morbidity and mortality, is a priority. However, depending on the cause of the event, patient comorbidities, and other factors, the most effective therapeutic strategies may differ. For example, cardioembolic strokes, which constitute approximately 20% of ischemic strokes, are treated with anticoagulants, whereas strokes of noncardioembolic origin are usually treated with antiplatelet agents.7, 8 Other risk factors or variables such as recent stent placement or reduced left ventricular ejection fraction (LVEF) may affect therapeutic decisions as well, although in many cases clear data are not available to direct these difficult decisions. Thus, although antiplatelet agents, including aspirin, clopidogrel, and aspirin plus extended‐release dipyridamole, prevent strokes, the choice of agent depends on the individual patient risk profile. A number of challenging patient scenarios are explored in this article with the goal of providing a context for some of the more recent trial data.

RECENT STENT PLACEMENT

In 2004, there were approximately 663,000 percutaneous coronary interventions (PCIs).9 Stenting after PCI is a common procedure and is used in more than 70% of coronary angioplasty procedures. The addition of stenting to the PCI procedure has improved the outcome for patients, reducing the need for revascularization.10 Because restenosis of the area following stent placement is common, drug‐eluting stents are also used to allow slow release of antiproliferative agents such as sirolimus or paclitaxel.11, 12

Studies such as Percutaneous Coronary InterventionClopidogrel in Unstable Angina to Prevent Recurrent Events (PCI‐CURE) and Clopidogrel for Reduction of Events During Observation (CREDO) have supported the use of up to 8 months of clopidogrel plus aspirin following coronary interventions.13, 14 The European Society of Cardiology PCI guidelines state that in regard to PCI procedures, clopidogrel is superior to aspirin. The guidelines recommend 34 weeks of clopidogrel following stenting in patients with stable angina but up to 12 months in patients receiving brachytherapy. Among patients who have received drug‐eluting stents, clopidogrel therapy should be continued for 612 months. In contrast, aspirin therapy (75100 mg/day) should be continued for life in all these patients.10 In patients who have had a nonST segment elevation myocardial infarction (MI) or who have unstable angina, these guidelines recommend the continuation of clopidogrel (75 mg/day) plus aspirin (100 mg/day) for 912 months after a PCI procedure.10

However, although clopidogrel plus aspirin reduces the incidence of major ischemic events in the period immediately following a stenting procedure, some have suggested that long‐term use of clopidogrel is not supported by the evidence.14 It has been proposed that the sustained beneficial effect of clopidogrel given in the immediate postoperative period may account for much of the long‐term benefit, as has been shown to be true of the glycoprotein IIb/IIIa antagonists.14 However, others caution that in the case of drug‐eluting stents, inhibition of endothelialization of the stent struts by the embedded agents makes these stents more susceptible to thrombosis formation, particularly if therapy with clopidogrel plus aspirin is interrupted.12 It is believed that late stent thrombosis, which has a high mortality rate, is more common with drug‐eluting stents than with bare‐metal stents.12, 15 As a result, many cardiologists recommend at least 12 months of dual antiplatelet therapy with aspirin plus clopidogrel for patients who have received drug‐eluting stents.12 However, given the results of the recent Management of Atherothrombosis in High‐risk Patients with Recent Transient Ischemic Attack or Ischemic Stroke (MATCH) and Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trials,16, 17 in particular, the high incidence of bleeding events in the clopidogrel plus aspirin group, there are concerns about longer‐term or lifelong therapy with this combination in a population at risk for recurrent stroke.

What about the patient who has undergone a coronary stent placement in the past 12 months and experiences a subsequent ischemic stroke or TIA? The patient should be continued on clopidogrel plus aspirin for the recommended time, as premature discontinuation of antiplatelet therapy increases the risk of stent thrombosis.18 No data are currently available to support decision making regarding these patients. However, it has been suggested that among patients given drug‐eluting stents, extended use of clopidogrel at 6, 12, and 24 months is associated with reduced risk of death or death/MI.18

LOW EJECTION FRACTION

Patients who have had a stroke or TIA and have underlying left ventricular dysfunction are at increased risk of a cardioembolic stroke.8 The reduction in stroke volume creates a condition of stasis in the ventricle that increases the likelihood of coagulation and thromboembolic events.8, 19 Evidence indicates that the risk of stroke is inversely correlated with LVEF; LVEF of 29%35% carries a cumulative 5‐year stroke risk of 7.8%, and LVEF of 28% or below carries a 5‐year risk of 8.9%.8, 20, 21 Data from the Survival and Ventricular Enlargement (SAVE) study showed an 18% increase in the risk of stroke for every 5% decline in LVEF,19, 21 and the Studies of Left Ventricular Dysfunction (SOLVD) trial found a 58% increase in thromboembolic events for every 10% decrease in LVEF among women (P = .01).19, 22 Among patients with low LVEF who have had a stroke, the 5‐year recurrent stroke rate may be as high as 45%.19, 23

Although it would appear that stroke associated with left ventricular dysfunction and a low LVEF may potentially be cardioembolic in origin, risk reduction for recurrent stroke has not been adequately investigated as a primary end point in clinical trials, particularly in the absence of atrial fibrillation.24 Thus, the question of whether antiplatelet or anticoagulant therapy would be more effective has not yet been answered. However, results of secondary end point analyses in the SOLVD and SAVE trials suggested that patients had a lower risk of sudden death, thromboembolism, and stroke with antiplatelet therapy.21, 2426 In an observational analysis of prospectively collected data on patients enrolled in the SAVE trial, use of aspirin reduced the overall risk of stroke by 66% in patients with an LVEF below 28%.21 Warfarin is the standard of care for stroke prevention in atrial fibrillation, and the 2 conditions often coexist. In those patients, warfarin is the recommended therapy.24

In patients with sinus rhythm and a low LVEF, the choice is less clear. The results of the Warfarin/Aspirin Study in Heart failure (WASH) failed to establish efficacy or safety for aspirin in preventing all‐cause mortality, nonfatal MI, and nonfatal stroke in patients with heart failure. Patients treated with aspirin were significantly more likely to be hospitalized for cardiovascular events, especially worsening heart failure.27 The trial found no significant difference for the composite end point between the 3 treatment groups: aspirin, warfarin, or no antithrombotic treatment. However, this was a small trial, and the findings were far from definitive, as the study was designed primarily to be a feasibility study to aid in the design of a larger outcomes study.24 Because of the inconsistent results and lack of well‐designed studies regarding the benefit of aspirin or anticoagulation for secondary stroke prevention in patients with LVEF in the absence of atrial fibrillation, further study is needed.

More recently, results were presented from the Warfarin and Antiplatelet Therapy in Heart Failure Trial (WATCH), which randomized patients with heart failure, sinus rhythm, and LVEF of 35% or below to either aspirin 162 mg, warfarin (target international normalized ratio [INR] 2.53.0), or clopidogrel.28, 29 Two major comparisons were plannedwarfarin versus aspirin and aspirin versus clopidogrel.28 Whereas warfarin therapy was open‐label because of the need to check blood levels, antiplatelet therapy was given in a double‐blind manner. After a mean follow‐up of 23 months, no significant differences were found for the primary composite end point of all‐cause mortality, nonfatal MI, and nonfatal stroke, which occurred in 20.5% of those on aspirin, 19.8% on warfarin, and 21.8% on clopidogrel. However, for the secondary end point of stroke, there was a strong trend favoring warfarin over aspirin: stroke occurred in 0.7% of patients taking warfarin versus 2.1% of those taking aspirin (P = .06).24, 29 However, the WATCH investigators concluded that the question of warfarin's value for patients with low LVEF and sinus rhythm remained unresolved.29

In the absence of clear data, the American Heart Association (AHA)/American Stroke Association (ASA) guidelines on stroke prevention in this patient population recommend either warfarin (INR 2.03.0) or antiplatelet therapy, including aspirin (50325 mg/day), aspirin plus extended‐release dipyridamole (200 mg twice daily), or clopidogrel (75 mg/day).8 Patients with coexisting atrial fibrillation should be treated with warfarin, or if unable to tolerate that agent, aspirin 325 mg/day.8

The Warfarin Versus Aspirin for Reduced Cardiac Ejection Fraction (WARCEF) trial may provide more definitive answers on the best approach for reducing the risk of recurrent stroke in patients with low LVEF. The study will compare warfarin (INR 2.53.0) and aspirin (325 mg/day) in the prevention of all‐cause mortality and all strokes (ischemic and hemorrhagic) in patients with an LVEF of 35% or below but no atrial fibrillation.30 The study has a target enrollment of 2860 patients, who are being recruited at 70 North American and 70 European sites, and it will include patients with recent stroke or TIA.28 The results are anxiously anticipated.

INTRACRANIAL STENOSIS

Stroke patients with symptomatic intracranial atherosclerosis have a high risk of recurrent strokein the range of 10% per yearand this accounts for approximately 8% of ischemic strokes.8, 31, 32 Intracranial stenosis appears to be more common in African Americans and Hispanics than in white patients.31

Recurrent stroke prevention in patients with intracranial stenosis was explored in the Warfarin‐Aspirin Symptomatic Intracranial Disease (WASID) study, a multicenter, double‐blind trial. Patients with angiographically verified 50%99% stenosis of a major intracranial artery who had experienced either a stroke or TIA were randomized to either warfarin (target INR 2.03.0) or high‐dose aspirin (1300 mg/day). The primary end point was ischemic stroke, brain hemorrhage, or death from vascular causes other than stroke.33 Mean follow‐up was 1.8 years, and enrollment was stopped after 569 patients had been randomized because of concerns about the safety of warfarin in this patient population.33 The primary end point occurred in 22.1% of those treated with aspirin and 21.8% of those treated with warfarin.33 There were no significant differences between the 2 treatment groups for any of the prespecified secondary end points, including ischemic stroke in any vascular territory and ischemic stroke in the territory of the stenotic intracranial artery.33

The rate of death was significantly higher in the warfarin group (9.7%) than in the aspirin group (4.3%; P = .02). Patients in the warfarin group had higher rates of death from both vascular and nonvascular causes.33 Major hemorrhage was significantly more common in the warfarin group (8.3%) than in the aspirin group (3.2%; P = .01). The investigators concluded that warfarin should not be used as first‐line prevention of recurrent stroke in patients with intracranial stenosis. However, there was a significant association between an INR less than 2 and increased risk of ischemic stroke and major cardiac events (P < .001) as well as a significant increase in major hemorrhages in patients with INRs greater than 3 (P < .001).33

The failure of many patients in the study to remain within the therapeutic INR casts doubt on these results to some extent, although this may actually mirror a common real‐world scenario. Patients were within the therapeutic INR goal only 63% of the time. Furthermore, a nonstandard high dose of aspirin (1300 mg/day) was used, which also may have affected the results.34 Others looking at this data have suggested that aspirin remains an imperfect therapy, with an unacceptably high risk of ischemic stroke and other vascular events, and that anticoagulation may play a role in the period immediately following ischemic stroke or TIA with transition to antiplatelet therapy.34 This would require additional investigation.34

The current AHA/ASA guidelines recommend that for patients with noncardioembolic ischemic stroke or TIA, antiplatelet agents rather than oral anticoagulants be used to reduce the risk of recurrent stroke (class I, level A). Aspirin (50325 mg/day), the combination of aspirin and extended‐release dipyridamole, and clopidogrel are all acceptable options for initial therapy (class IIa, level A).8 The combination of aspirin and extended‐release dipyridamole is suggested instead of aspirin alone (class IIa, level A), and clopidogrel may be considered instead of aspirin alone (class IIb, level B).8 However, data are insufficient at this point to make evidence‐based recommendations between antiplatelet options other than aspirin.8 In patients with significant intracranial stenosis whose symptoms persist despite medical therapy, including antithrombotics, statins, and antihypertensives, endovascular therapy with angioplasty and/or stent placement is an option, but it remains investigational and its value is uncertain.8

CAROTID STENOSIS

Asymptomatic carotid stenosis greater than 50% has been found in 7% of men and 5% of women older than 65 years.35, 36 Among those with asymptomatic carotid stenosis greater than 50%, there is an annual risk of stroke of up to 3.4%.35 In such patients, the benefit of carotid endarterectomy (CEA) is highly dependent on the surgical risk, and if complication rates exceed 3.0%, benefit is eliminated.35 The AHA/ASA guidelines recommend that patients be given treatment for all identifiable risk factors, including statins for dyslipidemia, antihypertensives for hypertension, and aspirin as an antiplatelet agent. In select patients with high‐grade asymptomatic carotid stenosis, CEA performed by a surgeon with a morbidity/mortality rate below 3% is recommended.35 In asymptomatic patients with greater than 70% carotid stenosis, CEA can be an effective therapy. Trial data indicate that the overall 5‐year risk of any stroke or perioperative death is 11.8% for deferred surgery versus 6.4% for immediate endarterectomy (P < .0001).35, 37 Unfortunately, data on the value of stents or angioplasty compared with CEA in this patient population are limited.35

In patients who have had a recent TIA or stroke, carotid stenosis would be considered symptomatic. In these patients, the benefit of CEA is strongly associated with the degree of stenosis. Data from the Carotid Endarterectomy Trialists' Collaboration and North American Symptomatic Carotid Endarterectomy Trial (NASCET) have shown that in patients with stenosis greater than 70%, CEA reduces the absolute 5‐year risk of ischemic stroke by 16.0% (P < .001), whereas in patients with 50%69% stenosis, the 5‐year absolute risk reduction is 4.6% (P = .04). In those with stenosis of 30%49%, there is no effect, and CEA in patients with less than 30% stenosis increases the risk of stroke.38, 39 In patients with 50%69% stenosis, benefit is achieved only if patients at highest risk are selected.40 Recent data have also questioned the typical 4‐ to 6‐week delay before performing a CEA following a nondisabling stroke. Rothwell et al. found that surgery performed within 2 weeks of such a stroke was not associated with increased operative risk.41 Moreover, benefit from CEA fell rapidly within the first few weeks after a TIA or stroke, particularly in women, perhaps reflecting the high risk of recurrent stroke in the period immediately following an initial event.41

Angioplasty or stents have been investigated as alternatives to CEA, but the evidence to date has been disappointing. The Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) demonstrated preventive efficacy and major risks similar to those found for CEA after 3 years of follow‐up in 504 patients with carotid stenosis.42 However, a more recent study was stopped prematurely after 527 patients had been enrolled because of a higher incidence of disabling stroke or death at 30 days in the stenting cohort (3.4%) compared with the CEA cohort (1.5%). The 30‐day incidence of any stroke or death was 3.9% after CEA and 9.6% after stenting, yielding a relative risk of 2.5 for stenting.43 The Stent‐Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients (SPACE) trial has also failed to find benefit for carotid stenting and/or angioplasty in comparison with CEA.44

The AHA/ASA guidelines recommend CEA in patients with ipsilateral severe (70%99%) stenosis and a recent TIA or ischemic stroke (within 6 months). Surgery should be performed by a surgeon with a perioperative morbidity/mortality rate less than 6%.8 In patients with 50%69% stenosis, the advisability of CEA depends on patient factors such as age, sex, comorbidities, and severity of symptoms. Surgery should be performed within 2 weeks of an ischemic event. In patients with severe stenosis in whom CEA would be difficult to perform, carotid angioplasty or stenting may be recommended if performed by practitioners with a morbidity/mortality rate less than 4%6%.8 The Seventh ACCP Conference also recommends that patients undergoing CEA receive aspirin 81325 mg/day prior to and following the procedure.7

ATHEROSCLEROSIS OF THE AORTIC ARCH

Atherosclerosis of the aortic arch contributes significantly as an independent factor to risk of embolic stroke.7 Such plaques can be detected using transesophageal echocardiography; those that are thicker than 45 mm, exhibit ulceration, or have mobile components place individuals at higher risk for stroke.7, 45 The stroke risk associated with aortic arch plaques greater than 5 mm is as high as 33% per year.7, 46

However, data from large‐scale randomized clinical trials on the efficacy of therapeutic interventions in this condition are lacking. Two small trials found efficacy for warfarin in patients with mobile thrombi in the thoracic aorta. In one, patients given oral anticoagulants had better outcomes than those treated with antiplatelet agents, and in the other, warfarin proved to be more effective than no treatment.47, 48 A retrospective trial that looked at 519 patients treated with warfarin, antiplatelet agents, or statins found there was a protective effect of statins, with an absolute risk reduction in embolic events, including ischemic stroke, TIA, and peripheral embolization of 17%, and a relative risk reduction in embolic events of 59%. The odds ratio for embolic events was 0.39 for statins, 0.77 for antiplatelet agents, and 1.18 for warfarin.49 The French Study of Aortic Plaque in Stroke found no significant difference in risk of events between those treated with warfarin and those treated with aspirin; however, this study was not designed as a therapeutic trial, and few patients received warfarin, casting doubt on this finding.45

Given the paucity of data, suggestions for treatment of patients with an aortic arch atheromata are difficult. Certainly, statin therapy, which would address general atherosclerotic risk reduction, can be initiated. Warfarin appeared to be more effective than antiplatelet agents in several of the studies; however some have expressed concern about the possibility of anticoagulation increasing the risk of cholesterol embolism in these patients.7

SYMPTOMATIC CORONARY ARTERY DISEASE

For patients with a history of ischemic stroke or TIA who have symptomatic CAD, their condition must be managed for both stroke and CAD risks. In patients with stable or unstable angina and a history of stroke or TIA, similar risks must be managed. The acute treatment of ACS or symptomatic CAD cannot be adequately addressed here; however, it may involve a number of therapeutic modalities, including PCI, ‐blocker therapy, glycoprotein IIb/IIIa inhibitors, anticoagulant therapy, angiotensin‐converting enzyme (ACE) inhibitors, and clopidogrel plus aspirin, depending on the exact nature of the syndrome.5054 The long‐term management and, in particular, prevention of recurrent stroke in the setting of symptomatic CAD are the focus here. As with a patient with a history of CAD and a recent TIA or stroke (as discussed earlier), patients with symptomatic CAD and TIA or stroke must be managed for multiple risk factors. NCEP guidelines recommend aggressive cholesterol lowering with statin therapy. Hypertension must be addressed as well, and long‐term therapy with ‐blockers and ACE inhibitors has been shown to reduce mortality in patients with ACS and is recommended by the AHA/ASA.5355

Once the acute ACS period has resolved, it is reasonable to address the question of the best possible antiplatelet therapy for long‐term stroke prevention. Long‐term use of clopidogrel plus aspirin is not advisable given the increased risk of bleeding events noted in the MATCH and CHARISMA trials.16, 17 At this point, it would be reasonable to start the patient on aspirin 75150 mg/day, which reduces risk of stroke up to 25%,56, 57 aspirin plus extended‐release dipyridamole, which reduces risk by about 37%,57, 58 or clopidogrel 75 mg/day, which reduces the relative risk for stroke alone by 7.3% compared with aspirin.59 In patients who cannot tolerate or are allergic to aspirin, clopidogrel is a reasonable choice.8

ANTIPLATELET FAILURE

Patients who have failed antiplatelet therapythat is, have gone on to have a recurrent strokeare particularly difficult. It is important to remember that any therapeutic intervention only reduces stroke risk; it does not eliminate it. Keeping that in mind, it is essential to reevaluate and reconsider both the original diagnosis and the etiology of the stroke or TIA. A number of diagnostic alternatives should be considered, including sensory seizure and migraine equivalents, as well as other etiologies, such as atrial fibrillation or cerebral amyloid angiopathy. Therapy may have to be adjusted accordingly, but the patient remains at increased risk for stroke recurrence, and thus preventive therapy is critical.

Several key points should be remembered. As outlined previously in this article, if the stroke is still thought to be noncardioembolic in origin, a reduction in the risk of stroke has not been found for those patients receiving warfarin, an increased dose of aspirin, a combination of antiplatelet agents and warfarin, or clopidogrel plus aspirin.8, 16, 31, 60, 61 However, if atrial fibrillation has developed in the patient, the recommendation is warfarin (INR 2.03.0) or, if anticoagulants cannot be taken, aspirin 325 mg/day.8 Risk factors should be reassessed and managed, with agents and lifestyle changes to control hypertension and dyslipidemia. Antiplatelet agents should be continued in patients with noncardioembolic stroke. Acceptable antiplatelet agents include aspirin (50325 mg/day), aspirin plus extended‐release dipyridamole, and clopidogrel. The combination of aspirin plus extended‐release dipyridamole is suggested over aspirin alone. If the patient cannot tolerate or is allergic to aspirin, clopidogrel is a reasonable alternative.8 The decision of which antiplatelet agent to use should be based on the individual patient's risk factor profile.8 The temptation to put patients on anticoagulation therapy because of a wish to do more should be avoided, as this is likely to expose patients to increased risk without known benefit.60, 61

Consider a common case scenarioa patient with a known history of hypertension and TIA presents with a 30‐minute episode of left arm numbness. The patient has been adherent to his prescribed medications, including aspirin 81 mg/day. What is the appropriate approach to acute treatment at this time? This is a common scenario in emergency departmentsnew‐onset TIA while taking aspirin 81 mg/day. There are advocates for several different treatment regimens in these patients: increasing the aspirin dose to 325 mg/day as a new treatment; discontinuing aspirin and initiating clopidogrel 75 mg/day; discontinuing aspirin 81 mg/day and initiating aspirin 325 mg/day plus clopidogrel 75 mg/day; or discontinuing aspirin 81 mg/day and initiating a combination of aspirin 25 mg plus extended‐release dipyridamole 200 mg twice daily. It is clear that patients with the same disease are treated differently in different institutions. What is the appropriate evidence‐based treatment in this case? The answer is clearno evidence supports increasing the dose of aspirin as a new treatment for this case or initiating aspirin 325 mg/day plus clopidogrel 75 mg/day.16, 17 Based on the literature, for a patient who has recently had another cerebral ischemic event while on treatment, it would make sense to consider switching to another agent. Three agents are recommended by the guidelines: aspirin, clopidogrel, and aspirin plus extended‐release dipyridamole. If treatment 1 were to fail, it would not be against the evidence to initiate treatment 2 or 3.

PATIENTS ON WARFARIN

Data from the Warfarin‐Aspirin Recurrent Stroke Study (WARSS), a large‐scale recurrent stroke prevention trial conducted in 2206 patients, demonstrated that there was no survival benefit for noncardioembolic stroke survivors who were treated with warfarin.60, 61 Yet there are patients still taking warfarin to reduce stroke risk who do not have atrial fibrillation. Unless a patient is allergic to or intolerant of antiplatelet agents such as aspirin, clopidogrel, or dipyridamole, they should not be treated with warfarin for noncardioembolic stroke risk.8 The results of other studies of anticoagulation in recurrent stroke prevention, including the European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT),62 the Stroke Performance for Reporting the Improvement and Translation (SPIRIT) trial,63 and the WASID study,33 have yet to demonstrate a role for warfarin in prevention of noncardioembolic stroke.

Given these trial results, patients currently on warfarin who do not have a cardioembolic risk factor should be placed on antiplatelet therapy with aspirin, aspirin plus extended‐release dipyridamole, or clopidogrel 35 days after discontinuing warfarin therapy. However, it would be advisable to evaluate these patients for atrial fibrillation, as patients with that risk factor should remain on warfarin.8

SUMMARY

In clinical practice, health care providers often must manage patients with complex profiles. Multiple risk factors and comorbidities complicate treatment of these individuals, and robust clinical data are often lacking as clinical trials rarely include such individuals. Guidelines offer recommendations, but these too are often based on extrapolations from clinical trial data. This is particularly true of patients at risk for ischemic stroke, as the primary underlying causevascular diseasehas systemic implications and comorbidities that often complicate treatment.

In general, antiplatelet therapy should be used to prevent recurrent stroke in patients with TIA or noncardioembolic stroke, whereas anticoagulation therapy should be used in patients with cardioembolic stroke such as that caused by atrial fibrillation. However, therapy must be individualized to account for the patient's full risk profile. Conditions such as dyslipidemia and hypertension must be addressed as well, as these not only give rise to stroke but also to the CAD, coronary heart disease, and ACS that may coexist with stroke. Among patients deemed suitable for antiplatelet therapy, class IIa, level A evidence supports the use of aspirin 50325 mg/day, the combination of aspirin and extended‐release dipyridamole, and clopidogrel for secondary prevention of stroke.8

The risk of recurrent stroke is high following an ischemic stroke or transient ischemic attack (TIA).16 Within the first 90 days following an initial TIA, between 4.8% and 18.3% of individuals will have an ischemic stroke, with many experiencing an ischemic event within the first 27 days.14 The risk of subsequent stroke in a stroke survivor is high as well4.2% at 6 months, 6.5% at 1 year, and 11.8% at 3 years.5 The management of these patients poses substantial challenges for the health care professional. Prevention of secondary stroke, with its risk for greater morbidity and mortality, is a priority. However, depending on the cause of the event, patient comorbidities, and other factors, the most effective therapeutic strategies may differ. For example, cardioembolic strokes, which constitute approximately 20% of ischemic strokes, are treated with anticoagulants, whereas strokes of noncardioembolic origin are usually treated with antiplatelet agents.7, 8 Other risk factors or variables such as recent stent placement or reduced left ventricular ejection fraction (LVEF) may affect therapeutic decisions as well, although in many cases clear data are not available to direct these difficult decisions. Thus, although antiplatelet agents, including aspirin, clopidogrel, and aspirin plus extended‐release dipyridamole, prevent strokes, the choice of agent depends on the individual patient risk profile. A number of challenging patient scenarios are explored in this article with the goal of providing a context for some of the more recent trial data.

RECENT STENT PLACEMENT

In 2004, there were approximately 663,000 percutaneous coronary interventions (PCIs).9 Stenting after PCI is a common procedure and is used in more than 70% of coronary angioplasty procedures. The addition of stenting to the PCI procedure has improved the outcome for patients, reducing the need for revascularization.10 Because restenosis of the area following stent placement is common, drug‐eluting stents are also used to allow slow release of antiproliferative agents such as sirolimus or paclitaxel.11, 12

Studies such as Percutaneous Coronary InterventionClopidogrel in Unstable Angina to Prevent Recurrent Events (PCI‐CURE) and Clopidogrel for Reduction of Events During Observation (CREDO) have supported the use of up to 8 months of clopidogrel plus aspirin following coronary interventions.13, 14 The European Society of Cardiology PCI guidelines state that in regard to PCI procedures, clopidogrel is superior to aspirin. The guidelines recommend 34 weeks of clopidogrel following stenting in patients with stable angina but up to 12 months in patients receiving brachytherapy. Among patients who have received drug‐eluting stents, clopidogrel therapy should be continued for 612 months. In contrast, aspirin therapy (75100 mg/day) should be continued for life in all these patients.10 In patients who have had a nonST segment elevation myocardial infarction (MI) or who have unstable angina, these guidelines recommend the continuation of clopidogrel (75 mg/day) plus aspirin (100 mg/day) for 912 months after a PCI procedure.10

However, although clopidogrel plus aspirin reduces the incidence of major ischemic events in the period immediately following a stenting procedure, some have suggested that long‐term use of clopidogrel is not supported by the evidence.14 It has been proposed that the sustained beneficial effect of clopidogrel given in the immediate postoperative period may account for much of the long‐term benefit, as has been shown to be true of the glycoprotein IIb/IIIa antagonists.14 However, others caution that in the case of drug‐eluting stents, inhibition of endothelialization of the stent struts by the embedded agents makes these stents more susceptible to thrombosis formation, particularly if therapy with clopidogrel plus aspirin is interrupted.12 It is believed that late stent thrombosis, which has a high mortality rate, is more common with drug‐eluting stents than with bare‐metal stents.12, 15 As a result, many cardiologists recommend at least 12 months of dual antiplatelet therapy with aspirin plus clopidogrel for patients who have received drug‐eluting stents.12 However, given the results of the recent Management of Atherothrombosis in High‐risk Patients with Recent Transient Ischemic Attack or Ischemic Stroke (MATCH) and Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trials,16, 17 in particular, the high incidence of bleeding events in the clopidogrel plus aspirin group, there are concerns about longer‐term or lifelong therapy with this combination in a population at risk for recurrent stroke.

What about the patient who has undergone a coronary stent placement in the past 12 months and experiences a subsequent ischemic stroke or TIA? The patient should be continued on clopidogrel plus aspirin for the recommended time, as premature discontinuation of antiplatelet therapy increases the risk of stent thrombosis.18 No data are currently available to support decision making regarding these patients. However, it has been suggested that among patients given drug‐eluting stents, extended use of clopidogrel at 6, 12, and 24 months is associated with reduced risk of death or death/MI.18

LOW EJECTION FRACTION

Patients who have had a stroke or TIA and have underlying left ventricular dysfunction are at increased risk of a cardioembolic stroke.8 The reduction in stroke volume creates a condition of stasis in the ventricle that increases the likelihood of coagulation and thromboembolic events.8, 19 Evidence indicates that the risk of stroke is inversely correlated with LVEF; LVEF of 29%35% carries a cumulative 5‐year stroke risk of 7.8%, and LVEF of 28% or below carries a 5‐year risk of 8.9%.8, 20, 21 Data from the Survival and Ventricular Enlargement (SAVE) study showed an 18% increase in the risk of stroke for every 5% decline in LVEF,19, 21 and the Studies of Left Ventricular Dysfunction (SOLVD) trial found a 58% increase in thromboembolic events for every 10% decrease in LVEF among women (P = .01).19, 22 Among patients with low LVEF who have had a stroke, the 5‐year recurrent stroke rate may be as high as 45%.19, 23

Although it would appear that stroke associated with left ventricular dysfunction and a low LVEF may potentially be cardioembolic in origin, risk reduction for recurrent stroke has not been adequately investigated as a primary end point in clinical trials, particularly in the absence of atrial fibrillation.24 Thus, the question of whether antiplatelet or anticoagulant therapy would be more effective has not yet been answered. However, results of secondary end point analyses in the SOLVD and SAVE trials suggested that patients had a lower risk of sudden death, thromboembolism, and stroke with antiplatelet therapy.21, 2426 In an observational analysis of prospectively collected data on patients enrolled in the SAVE trial, use of aspirin reduced the overall risk of stroke by 66% in patients with an LVEF below 28%.21 Warfarin is the standard of care for stroke prevention in atrial fibrillation, and the 2 conditions often coexist. In those patients, warfarin is the recommended therapy.24

In patients with sinus rhythm and a low LVEF, the choice is less clear. The results of the Warfarin/Aspirin Study in Heart failure (WASH) failed to establish efficacy or safety for aspirin in preventing all‐cause mortality, nonfatal MI, and nonfatal stroke in patients with heart failure. Patients treated with aspirin were significantly more likely to be hospitalized for cardiovascular events, especially worsening heart failure.27 The trial found no significant difference for the composite end point between the 3 treatment groups: aspirin, warfarin, or no antithrombotic treatment. However, this was a small trial, and the findings were far from definitive, as the study was designed primarily to be a feasibility study to aid in the design of a larger outcomes study.24 Because of the inconsistent results and lack of well‐designed studies regarding the benefit of aspirin or anticoagulation for secondary stroke prevention in patients with LVEF in the absence of atrial fibrillation, further study is needed.

More recently, results were presented from the Warfarin and Antiplatelet Therapy in Heart Failure Trial (WATCH), which randomized patients with heart failure, sinus rhythm, and LVEF of 35% or below to either aspirin 162 mg, warfarin (target international normalized ratio [INR] 2.53.0), or clopidogrel.28, 29 Two major comparisons were plannedwarfarin versus aspirin and aspirin versus clopidogrel.28 Whereas warfarin therapy was open‐label because of the need to check blood levels, antiplatelet therapy was given in a double‐blind manner. After a mean follow‐up of 23 months, no significant differences were found for the primary composite end point of all‐cause mortality, nonfatal MI, and nonfatal stroke, which occurred in 20.5% of those on aspirin, 19.8% on warfarin, and 21.8% on clopidogrel. However, for the secondary end point of stroke, there was a strong trend favoring warfarin over aspirin: stroke occurred in 0.7% of patients taking warfarin versus 2.1% of those taking aspirin (P = .06).24, 29 However, the WATCH investigators concluded that the question of warfarin's value for patients with low LVEF and sinus rhythm remained unresolved.29

In the absence of clear data, the American Heart Association (AHA)/American Stroke Association (ASA) guidelines on stroke prevention in this patient population recommend either warfarin (INR 2.03.0) or antiplatelet therapy, including aspirin (50325 mg/day), aspirin plus extended‐release dipyridamole (200 mg twice daily), or clopidogrel (75 mg/day).8 Patients with coexisting atrial fibrillation should be treated with warfarin, or if unable to tolerate that agent, aspirin 325 mg/day.8

The Warfarin Versus Aspirin for Reduced Cardiac Ejection Fraction (WARCEF) trial may provide more definitive answers on the best approach for reducing the risk of recurrent stroke in patients with low LVEF. The study will compare warfarin (INR 2.53.0) and aspirin (325 mg/day) in the prevention of all‐cause mortality and all strokes (ischemic and hemorrhagic) in patients with an LVEF of 35% or below but no atrial fibrillation.30 The study has a target enrollment of 2860 patients, who are being recruited at 70 North American and 70 European sites, and it will include patients with recent stroke or TIA.28 The results are anxiously anticipated.

INTRACRANIAL STENOSIS

Stroke patients with symptomatic intracranial atherosclerosis have a high risk of recurrent strokein the range of 10% per yearand this accounts for approximately 8% of ischemic strokes.8, 31, 32 Intracranial stenosis appears to be more common in African Americans and Hispanics than in white patients.31

Recurrent stroke prevention in patients with intracranial stenosis was explored in the Warfarin‐Aspirin Symptomatic Intracranial Disease (WASID) study, a multicenter, double‐blind trial. Patients with angiographically verified 50%99% stenosis of a major intracranial artery who had experienced either a stroke or TIA were randomized to either warfarin (target INR 2.03.0) or high‐dose aspirin (1300 mg/day). The primary end point was ischemic stroke, brain hemorrhage, or death from vascular causes other than stroke.33 Mean follow‐up was 1.8 years, and enrollment was stopped after 569 patients had been randomized because of concerns about the safety of warfarin in this patient population.33 The primary end point occurred in 22.1% of those treated with aspirin and 21.8% of those treated with warfarin.33 There were no significant differences between the 2 treatment groups for any of the prespecified secondary end points, including ischemic stroke in any vascular territory and ischemic stroke in the territory of the stenotic intracranial artery.33

The rate of death was significantly higher in the warfarin group (9.7%) than in the aspirin group (4.3%; P = .02). Patients in the warfarin group had higher rates of death from both vascular and nonvascular causes.33 Major hemorrhage was significantly more common in the warfarin group (8.3%) than in the aspirin group (3.2%; P = .01). The investigators concluded that warfarin should not be used as first‐line prevention of recurrent stroke in patients with intracranial stenosis. However, there was a significant association between an INR less than 2 and increased risk of ischemic stroke and major cardiac events (P < .001) as well as a significant increase in major hemorrhages in patients with INRs greater than 3 (P < .001).33

The failure of many patients in the study to remain within the therapeutic INR casts doubt on these results to some extent, although this may actually mirror a common real‐world scenario. Patients were within the therapeutic INR goal only 63% of the time. Furthermore, a nonstandard high dose of aspirin (1300 mg/day) was used, which also may have affected the results.34 Others looking at this data have suggested that aspirin remains an imperfect therapy, with an unacceptably high risk of ischemic stroke and other vascular events, and that anticoagulation may play a role in the period immediately following ischemic stroke or TIA with transition to antiplatelet therapy.34 This would require additional investigation.34

The current AHA/ASA guidelines recommend that for patients with noncardioembolic ischemic stroke or TIA, antiplatelet agents rather than oral anticoagulants be used to reduce the risk of recurrent stroke (class I, level A). Aspirin (50325 mg/day), the combination of aspirin and extended‐release dipyridamole, and clopidogrel are all acceptable options for initial therapy (class IIa, level A).8 The combination of aspirin and extended‐release dipyridamole is suggested instead of aspirin alone (class IIa, level A), and clopidogrel may be considered instead of aspirin alone (class IIb, level B).8 However, data are insufficient at this point to make evidence‐based recommendations between antiplatelet options other than aspirin.8 In patients with significant intracranial stenosis whose symptoms persist despite medical therapy, including antithrombotics, statins, and antihypertensives, endovascular therapy with angioplasty and/or stent placement is an option, but it remains investigational and its value is uncertain.8

CAROTID STENOSIS

Asymptomatic carotid stenosis greater than 50% has been found in 7% of men and 5% of women older than 65 years.35, 36 Among those with asymptomatic carotid stenosis greater than 50%, there is an annual risk of stroke of up to 3.4%.35 In such patients, the benefit of carotid endarterectomy (CEA) is highly dependent on the surgical risk, and if complication rates exceed 3.0%, benefit is eliminated.35 The AHA/ASA guidelines recommend that patients be given treatment for all identifiable risk factors, including statins for dyslipidemia, antihypertensives for hypertension, and aspirin as an antiplatelet agent. In select patients with high‐grade asymptomatic carotid stenosis, CEA performed by a surgeon with a morbidity/mortality rate below 3% is recommended.35 In asymptomatic patients with greater than 70% carotid stenosis, CEA can be an effective therapy. Trial data indicate that the overall 5‐year risk of any stroke or perioperative death is 11.8% for deferred surgery versus 6.4% for immediate endarterectomy (P < .0001).35, 37 Unfortunately, data on the value of stents or angioplasty compared with CEA in this patient population are limited.35

In patients who have had a recent TIA or stroke, carotid stenosis would be considered symptomatic. In these patients, the benefit of CEA is strongly associated with the degree of stenosis. Data from the Carotid Endarterectomy Trialists' Collaboration and North American Symptomatic Carotid Endarterectomy Trial (NASCET) have shown that in patients with stenosis greater than 70%, CEA reduces the absolute 5‐year risk of ischemic stroke by 16.0% (P < .001), whereas in patients with 50%69% stenosis, the 5‐year absolute risk reduction is 4.6% (P = .04). In those with stenosis of 30%49%, there is no effect, and CEA in patients with less than 30% stenosis increases the risk of stroke.38, 39 In patients with 50%69% stenosis, benefit is achieved only if patients at highest risk are selected.40 Recent data have also questioned the typical 4‐ to 6‐week delay before performing a CEA following a nondisabling stroke. Rothwell et al. found that surgery performed within 2 weeks of such a stroke was not associated with increased operative risk.41 Moreover, benefit from CEA fell rapidly within the first few weeks after a TIA or stroke, particularly in women, perhaps reflecting the high risk of recurrent stroke in the period immediately following an initial event.41

Angioplasty or stents have been investigated as alternatives to CEA, but the evidence to date has been disappointing. The Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) demonstrated preventive efficacy and major risks similar to those found for CEA after 3 years of follow‐up in 504 patients with carotid stenosis.42 However, a more recent study was stopped prematurely after 527 patients had been enrolled because of a higher incidence of disabling stroke or death at 30 days in the stenting cohort (3.4%) compared with the CEA cohort (1.5%). The 30‐day incidence of any stroke or death was 3.9% after CEA and 9.6% after stenting, yielding a relative risk of 2.5 for stenting.43 The Stent‐Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients (SPACE) trial has also failed to find benefit for carotid stenting and/or angioplasty in comparison with CEA.44

The AHA/ASA guidelines recommend CEA in patients with ipsilateral severe (70%99%) stenosis and a recent TIA or ischemic stroke (within 6 months). Surgery should be performed by a surgeon with a perioperative morbidity/mortality rate less than 6%.8 In patients with 50%69% stenosis, the advisability of CEA depends on patient factors such as age, sex, comorbidities, and severity of symptoms. Surgery should be performed within 2 weeks of an ischemic event. In patients with severe stenosis in whom CEA would be difficult to perform, carotid angioplasty or stenting may be recommended if performed by practitioners with a morbidity/mortality rate less than 4%6%.8 The Seventh ACCP Conference also recommends that patients undergoing CEA receive aspirin 81325 mg/day prior to and following the procedure.7

ATHEROSCLEROSIS OF THE AORTIC ARCH

Atherosclerosis of the aortic arch contributes significantly as an independent factor to risk of embolic stroke.7 Such plaques can be detected using transesophageal echocardiography; those that are thicker than 45 mm, exhibit ulceration, or have mobile components place individuals at higher risk for stroke.7, 45 The stroke risk associated with aortic arch plaques greater than 5 mm is as high as 33% per year.7, 46

However, data from large‐scale randomized clinical trials on the efficacy of therapeutic interventions in this condition are lacking. Two small trials found efficacy for warfarin in patients with mobile thrombi in the thoracic aorta. In one, patients given oral anticoagulants had better outcomes than those treated with antiplatelet agents, and in the other, warfarin proved to be more effective than no treatment.47, 48 A retrospective trial that looked at 519 patients treated with warfarin, antiplatelet agents, or statins found there was a protective effect of statins, with an absolute risk reduction in embolic events, including ischemic stroke, TIA, and peripheral embolization of 17%, and a relative risk reduction in embolic events of 59%. The odds ratio for embolic events was 0.39 for statins, 0.77 for antiplatelet agents, and 1.18 for warfarin.49 The French Study of Aortic Plaque in Stroke found no significant difference in risk of events between those treated with warfarin and those treated with aspirin; however, this study was not designed as a therapeutic trial, and few patients received warfarin, casting doubt on this finding.45

Given the paucity of data, suggestions for treatment of patients with an aortic arch atheromata are difficult. Certainly, statin therapy, which would address general atherosclerotic risk reduction, can be initiated. Warfarin appeared to be more effective than antiplatelet agents in several of the studies; however some have expressed concern about the possibility of anticoagulation increasing the risk of cholesterol embolism in these patients.7

SYMPTOMATIC CORONARY ARTERY DISEASE

For patients with a history of ischemic stroke or TIA who have symptomatic CAD, their condition must be managed for both stroke and CAD risks. In patients with stable or unstable angina and a history of stroke or TIA, similar risks must be managed. The acute treatment of ACS or symptomatic CAD cannot be adequately addressed here; however, it may involve a number of therapeutic modalities, including PCI, ‐blocker therapy, glycoprotein IIb/IIIa inhibitors, anticoagulant therapy, angiotensin‐converting enzyme (ACE) inhibitors, and clopidogrel plus aspirin, depending on the exact nature of the syndrome.5054 The long‐term management and, in particular, prevention of recurrent stroke in the setting of symptomatic CAD are the focus here. As with a patient with a history of CAD and a recent TIA or stroke (as discussed earlier), patients with symptomatic CAD and TIA or stroke must be managed for multiple risk factors. NCEP guidelines recommend aggressive cholesterol lowering with statin therapy. Hypertension must be addressed as well, and long‐term therapy with ‐blockers and ACE inhibitors has been shown to reduce mortality in patients with ACS and is recommended by the AHA/ASA.5355

Once the acute ACS period has resolved, it is reasonable to address the question of the best possible antiplatelet therapy for long‐term stroke prevention. Long‐term use of clopidogrel plus aspirin is not advisable given the increased risk of bleeding events noted in the MATCH and CHARISMA trials.16, 17 At this point, it would be reasonable to start the patient on aspirin 75150 mg/day, which reduces risk of stroke up to 25%,56, 57 aspirin plus extended‐release dipyridamole, which reduces risk by about 37%,57, 58 or clopidogrel 75 mg/day, which reduces the relative risk for stroke alone by 7.3% compared with aspirin.59 In patients who cannot tolerate or are allergic to aspirin, clopidogrel is a reasonable choice.8

ANTIPLATELET FAILURE

Patients who have failed antiplatelet therapythat is, have gone on to have a recurrent strokeare particularly difficult. It is important to remember that any therapeutic intervention only reduces stroke risk; it does not eliminate it. Keeping that in mind, it is essential to reevaluate and reconsider both the original diagnosis and the etiology of the stroke or TIA. A number of diagnostic alternatives should be considered, including sensory seizure and migraine equivalents, as well as other etiologies, such as atrial fibrillation or cerebral amyloid angiopathy. Therapy may have to be adjusted accordingly, but the patient remains at increased risk for stroke recurrence, and thus preventive therapy is critical.

Several key points should be remembered. As outlined previously in this article, if the stroke is still thought to be noncardioembolic in origin, a reduction in the risk of stroke has not been found for those patients receiving warfarin, an increased dose of aspirin, a combination of antiplatelet agents and warfarin, or clopidogrel plus aspirin.8, 16, 31, 60, 61 However, if atrial fibrillation has developed in the patient, the recommendation is warfarin (INR 2.03.0) or, if anticoagulants cannot be taken, aspirin 325 mg/day.8 Risk factors should be reassessed and managed, with agents and lifestyle changes to control hypertension and dyslipidemia. Antiplatelet agents should be continued in patients with noncardioembolic stroke. Acceptable antiplatelet agents include aspirin (50325 mg/day), aspirin plus extended‐release dipyridamole, and clopidogrel. The combination of aspirin plus extended‐release dipyridamole is suggested over aspirin alone. If the patient cannot tolerate or is allergic to aspirin, clopidogrel is a reasonable alternative.8 The decision of which antiplatelet agent to use should be based on the individual patient's risk factor profile.8 The temptation to put patients on anticoagulation therapy because of a wish to do more should be avoided, as this is likely to expose patients to increased risk without known benefit.60, 61

Consider a common case scenarioa patient with a known history of hypertension and TIA presents with a 30‐minute episode of left arm numbness. The patient has been adherent to his prescribed medications, including aspirin 81 mg/day. What is the appropriate approach to acute treatment at this time? This is a common scenario in emergency departmentsnew‐onset TIA while taking aspirin 81 mg/day. There are advocates for several different treatment regimens in these patients: increasing the aspirin dose to 325 mg/day as a new treatment; discontinuing aspirin and initiating clopidogrel 75 mg/day; discontinuing aspirin 81 mg/day and initiating aspirin 325 mg/day plus clopidogrel 75 mg/day; or discontinuing aspirin 81 mg/day and initiating a combination of aspirin 25 mg plus extended‐release dipyridamole 200 mg twice daily. It is clear that patients with the same disease are treated differently in different institutions. What is the appropriate evidence‐based treatment in this case? The answer is clearno evidence supports increasing the dose of aspirin as a new treatment for this case or initiating aspirin 325 mg/day plus clopidogrel 75 mg/day.16, 17 Based on the literature, for a patient who has recently had another cerebral ischemic event while on treatment, it would make sense to consider switching to another agent. Three agents are recommended by the guidelines: aspirin, clopidogrel, and aspirin plus extended‐release dipyridamole. If treatment 1 were to fail, it would not be against the evidence to initiate treatment 2 or 3.

PATIENTS ON WARFARIN

Data from the Warfarin‐Aspirin Recurrent Stroke Study (WARSS), a large‐scale recurrent stroke prevention trial conducted in 2206 patients, demonstrated that there was no survival benefit for noncardioembolic stroke survivors who were treated with warfarin.60, 61 Yet there are patients still taking warfarin to reduce stroke risk who do not have atrial fibrillation. Unless a patient is allergic to or intolerant of antiplatelet agents such as aspirin, clopidogrel, or dipyridamole, they should not be treated with warfarin for noncardioembolic stroke risk.8 The results of other studies of anticoagulation in recurrent stroke prevention, including the European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT),62 the Stroke Performance for Reporting the Improvement and Translation (SPIRIT) trial,63 and the WASID study,33 have yet to demonstrate a role for warfarin in prevention of noncardioembolic stroke.

Given these trial results, patients currently on warfarin who do not have a cardioembolic risk factor should be placed on antiplatelet therapy with aspirin, aspirin plus extended‐release dipyridamole, or clopidogrel 35 days after discontinuing warfarin therapy. However, it would be advisable to evaluate these patients for atrial fibrillation, as patients with that risk factor should remain on warfarin.8

SUMMARY

In clinical practice, health care providers often must manage patients with complex profiles. Multiple risk factors and comorbidities complicate treatment of these individuals, and robust clinical data are often lacking as clinical trials rarely include such individuals. Guidelines offer recommendations, but these too are often based on extrapolations from clinical trial data. This is particularly true of patients at risk for ischemic stroke, as the primary underlying causevascular diseasehas systemic implications and comorbidities that often complicate treatment.

In general, antiplatelet therapy should be used to prevent recurrent stroke in patients with TIA or noncardioembolic stroke, whereas anticoagulation therapy should be used in patients with cardioembolic stroke such as that caused by atrial fibrillation. However, therapy must be individualized to account for the patient's full risk profile. Conditions such as dyslipidemia and hypertension must be addressed as well, as these not only give rise to stroke but also to the CAD, coronary heart disease, and ACS that may coexist with stroke. Among patients deemed suitable for antiplatelet therapy, class IIa, level A evidence supports the use of aspirin 50325 mg/day, the combination of aspirin and extended‐release dipyridamole, and clopidogrel for secondary prevention of stroke.8