Susan C. Fagan and David C. Hess
KEY CONCEPTS
Stroke can be either ischemic (87%) or hemorrhagic (13%) and the two types are treated differently.
Transient ischemic attacks (TIAs) require urgent intervention to reduce the risk of stroke, which is known to be highest in the first few days after TIA.
Carotid endarterectomy should be performed in ischemic stroke patients with 70% to 99% stenosis of the ipsilateral carotid artery, provided that it is done in an experienced center.
Carotid stenting is an option for stroke patients eligible for carotid endarterectomy, especially in patients less than 70 years of age.
Early reperfusion (<4.5 hours from onset) with tissue plasminogen activator (tPA) has been shown to reduce the ultimate disability due to ischemic stroke.
Antiplatelet therapy is the cornerstone of antithrombotic therapy for the secondary prevention of noncardioembolic ischemic stroke.
Oral anticoagulation is recommended for the secondary prevention of cardioembolic stroke in moderate- to high-risk patients.
Blood pressure lowering is effective in both the primary and secondary prevention of both ischemic and hemorrhagic stroke regardless of blood pressure.
Blood pressure lowering in the acute ischemic stroke period (first 7 days) may result in decreased cerebral blood flow and worsened symptoms.
Statin therapy is recommended for all ischemic stroke patients, regardless of baseline cholesterol, to reduce stroke recurrence.
Stroke is the leading cause of disability among adults and the fourth leading cause of death in the United States, behind cardiovascular disease, cancer, and chronic lower respiratory diseases.1 Despite a 30% reduction in stroke mortality between 1995 and 2005, stroke occurs in the United States at a rate of almost 800,000 per year and resulted in 133,750,000 deaths in 2008.1,2 Aggressive efforts to organize stroke care at the local and regional levels and increased utilization of evidence-based recommendations and national guidelines may have contributed to the improved outcomes.
EPIDEMIOLOGY
There are currently 6.5 million stroke survivors in the United States, and stroke is the leading cause of adult disability.2 Of those free of the diagnosis of stroke or transient ischemic attack (TIA), however, almost 20% of individuals over the age of 45 years reported at least one stroke symptom,3 suggesting rampant underdiagnosing. Owing in part to the need for expensive posthospitalization rehabilitation and nursing home care, the annual cost of stroke in the United States is estimated to be $69 billion.2 Current projections are that death caused by stroke will increase exponentially in the next 30 years owing to aging of the population and our inability to control risk factors.4
African Americans have stroke rates that are twice those of whites, and the difference is exaggerated at younger ages.2 In addition, geographic disparity in stroke incidence exists, such that many states in the southeastern United States have stroke mortality rates 40% higher than the national average.2
Etiology
Stroke can be either ischemic or hemorrhagic (87% and 13%, respectively, of all strokes in the 2012 American Heart Association [AHA] report).2 Hemorrhagic strokes include subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), and subdural hematomas. SAH occurs when blood enters the subarachnoid space (where cerebrospinal fluid is housed) owing to trauma, rupture of an intracranial aneurysm, or rupture of an arteriovenous malformation (AVM). By contrast, ICH occurs when a blood vessel ruptures within the brain parenchyma itself, resulting in the formation of a hematoma. These types of hemorrhages very often are associated with uncontrolled high blood pressure and sometimes antithrombotic or thrombolytic therapy. Subdural hematomas refer to collections of blood below the dura (covering of the brain), and they are caused most often by trauma. Hemorrhagic stroke, although less common, is significantly more lethal than ischemic stroke, with 30-day case-fatality rates that are two to six times higher.5,6
Ischemic strokes are caused either by local thrombus formation or by embolic phenomena, resulting in occlusion of a cerebral artery. Atherosclerosis, particularly of the cerebral vasculature, is a causative factor in most cases of ischemic stroke, although 30% are cryptogenic. Emboli can arise from either intracranial or extracranial arteries (including the aortic arch) or, as is the case in 20% of all ischemic strokes, the heart. Cardiogenic embolism is presumed to have occurred if the patient has concomitant atrial fibrillation, valvular heart disease, or any other condition of the heart that can lead to clot formation.7Distinguishing between cardiogenic embolism and other causes of ischemic stroke is important in determining long-term pharmacotherapy in a given patient.
Risk Factors
Risk factors for stroke can be subdivided into nonmodifiable, modifiable, and potentially modifiable. In addition, risk factors can be either well documented or less well documented.8 The main risk factors of stroke are listed in Table 10-1. Recommendations for risk factor reduction aggressively target the modifiable, well-documented risk factors, even in individuals with nonmodifiable risk.8 The nonmodifiable risk factors are age, race, sex, low birth weight, and family history. An individual’s risk of having a stroke increases substantially as he or she ages, with a doubling of risk for each decade older than 55 years of age. African Americans, Asian-Pacific Islanders, and Hispanics experience higher death rates than their white counterparts.2 Men are at a higher risk of stroke than women when matched for age, but women who suffer from a stroke are more likely to die from it.2
TABLE 10-1 Risk Factors for Ischemic Stroke
The most common modifiable, well-documented risk factors for stroke include hypertension, cigarette smoking, diabetes, atrial fibrillation, and dyslipidemia. The treatment of hypertension, beginning in the mid-20th century, is thought to be primarily responsible for the drastic reduction in stroke death rates between 1950 and 1980 in the United States.4 A second very important risk factor for stroke is cardiac disease. Patients with coronary artery disease, congestive heart failure, left ventricular hypertrophy, and especially atrial fibrillation are at increased risk of stroke.8 In fact, the presence of atrial fibrillation is one of the most potent risk factors for ischemic stroke, with stroke rates from 5% to 20% per year depending on the patient’s comorbid conditions.9 Other known risk factors for atherosclerosis are also known to place patients at risk of stroke. Diabetes mellitus, dyslipidemia, and cigarette smoking are known atherogenic states that lead to cerebrovascular disease and ischemic stroke.9
PATHOPHYSIOLOGY
Ischemic Stroke
Ischemic stroke results from an occlusion of a cerebral artery, leading to a reduction in cerebral blood flow. The pathophysiologic mechanisms of ischemic stroke are given in Figure 10-1. Normal cerebral blood flow averages 50 mL/100 g per minute, and this is maintained over a wide range of blood pressures (mean arterial pressures of 50 to 150 mm Hg) by a process called cerebral autoregulation. Cerebral blood vessels dilate and constrict in response to changes in blood pressure, but this process can be impaired by atherosclerosis, chronic hypertension, and acute injury, such as stroke. Arterial occlusion leads to severe reductions in cerebral blood flow leading to infarction. Tissue that is ischemic but maintains membrane integrity is referred to as the ischemic penumbra because it usually surrounds the infarct core. This penumbra is potentially salvageable through therapeutic intervention.
FIGURE 10-1 Pathophysiology of ischemic stroke. Diagram illustrating the three major mechanisms underlying ischemic stroke including occlusion of an intracranial vessel by an embolus that arises from a distant site (e.g., cardiogenic embolus), in situ thrombosis of an intracranial vessel, typically affecting the small penetrating arteries, and hypoperfusion caused by flow-limiting stenosis of a major extracranial artery. (Reproduced with permission from Longo DL, Fauci AS, Kasper DL, et al. Harrison’s Principals and Practice of Internal Medicine, 18th ed. New York: McGraw-Hill, 2012.)
Reduction in the provision of nutrients to the ischemic cell eventually leads to depletion of the high-energy phosphates (e.g., adenosine triphosphate [ATP]) and accumulation of extracellular potassium, intracellular sodium, and water, leading to cell swelling and eventual lysis. The increase in intracellular calcium that follows results in the activation of lipases, proteases, and endonucleases and the release of free fatty acids from membrane phospholipids. In addition, there is a release of excitatory amino acids, such as glutamate and aspartate, that perpetuates the neuronal damage and the accumulation of free fatty acids, including arachidonic acid, and results in the formation of prostaglandins, leukotrienes, and free radicals. In ischemia, the magnitude of free radical production overwhelms normal scavenging systems, leaving these reactive molecules to attack cell membranes and contribute to the mounting intracellular acidosis. All these events occur within 2 to 3 hours of the onset of ischemia and contribute to the ultimate cell death.10
Later targets for intervention in the pathophysiologic process involved after cerebral ischemia include inflammation and apoptosis, or programmed cell death, occurring many hours after the acute insult and can interfere with recovery and repair of brain tissue.10
Hemorrhagic Stroke
The pathophysiology of hemorrhagic stroke is not as well studied as that of ischemic stroke. However, it is known that the presence of blood in the brain parenchyma causes damage to the surrounding tissue through the mechanical effect it produces (mass effect) and the neurotoxicity of the blood components and their degradation products.5,6 Approximately 30% of ICHs continue to enlarge over the first 24 hours, most within 4 hours, and clot volume is the most important predictor of outcome, regardless of location.11,12 Hemorrhage volumes >60 mL are associated with 71% to 93% mortality at 30 days.5,6 Much of the early mortality of hemorrhagic stroke (up to 50% at 30 days) is caused by the abrupt increase in intracranial pressure that can lead to herniation and death.1 There is also evidence to support that both early and late edema contributes to worsened outcome after ICH.6
CLINICAL PRESENTATION Stroke
General
• The patient may not be able to reliably report the history owing to cognitive or language deficits. A reliable history may have to come from a family member or another witness
Symptoms
• The patient may complain of weakness on one side of the body, inability to speak, loss of vision, vertigo, or falling. Ischemic stroke is not usually painful, but patients may complain of headache, and with hemorrhagic stroke, it can be very severe
Signs
• Patients usually have multiple signs of neurologic dysfunction, and the specific deficits are determined by the area of the brain involved
• Hemiparesis or monoparesis occurs commonly, as does a hemisensory deficit
• Patients with vertigo and double vision are likely to have posterior circulation involvement
• Aphasia is seen commonly in patients with anterior circulation strokes
• Patients may also suffer from dysarthria, visual field defects, and altered levels of consciousness
Laboratory Tests
• Tests for hypercoagulable states (protein C deficiency, antiphospholipid antibody) should be done only when the cause of the stroke cannot be determined based on the presence of well-known risk factors for stroke. Protein C, protein S, and antithrombin III are best measured in the “steady state,” not in the acute stage. Antiphospholipid antibodies as measured by anticardiolipin antibodies, β2-glycoprotein I, and lupus anticoagulant screen are of higher yield than protein C, protein S, and antithrombin III but should be reserved for patients who are young (<50 years of age), have had multiple venous/arterial thrombotic events, or have livedo reticularis (a skin rash)
Other Diagnostic Tests
• CT scan of the head will reveal an area of hyperintensity (white) in the area of hemorrhage and will be normal or hypointense (dark) in the area of infarction. The CT scan may take 24 hours (and rarely longer) to reveal the area of infarction
• MRI of the head will reveal areas of ischemia with higher resolution and earlier than the CT scan. Diffusion-weighted imaging (DWI) will reveal an evolving infarct within minutes
• Carotid Doppler (CD) studies will determine whether the patient has a high degree of stenosis in the carotid arteries supplying blood to the brain (extracranial disease)
• An electrocardiogram (ECG) will determine whether the patient has atrial fibrillation, a potent etiologic factor for stroke
• Transthoracic echocardiography (TTE) will determine whether valve abnormalities or wall-motion abnormalities are sources of emboli to the brain. A “bubble test” can be done to look for an intraatrial shunt indicating an atrial septal defect or a patent foramen ovale
• Transesophageal echocardiography (TEE) is a more sensitive test for thrombus in the left atrium. It is effective at examining the aortic arch for atheroma, a potential source of emboli
• Transcranial Doppler (TCD) will determine whether the patient is likely to have intracranial stenosis (e.g., middle cerebral artery stenosis)
CLINICAL PRESENTATION (INCLUDING DIAGNOSTIC CONSIDERATIONS)
Stroke is a term used to describe an abrupt-onset focal neurologic deficit that lasts at least 24 hours and is of presumed vascular origin. A TIA is the same but lasts less than 24 hours and usually less than 30 minutes. The abrupt onset and the duration of the symptoms are determined through the history. The use of sensitive imaging techniques (magnetic resonance imaging [MRI] with diffusion-weighted imaging [DWI]) has revealed that symptoms lasting more than 1 hour and less than 24 hours are associated with infarction, making TIA and minor stroke clinically indistinguishable. The location of the CNS injury and its reference to a specific arterial distribution in the brain are determined through the neurologic examination and confirmed by imaging studies such as computed tomography (CT) scanning and MRI. The main arterial supply to the cerebral hemispheres is illustrated in Figure 10-2. Further diagnostic tests are performed to identify the cause of the patient’s stroke and to design appropriate therapeutic strategies to prevent further events.13
FIGURE 10-2 Diagram of a cerebral hemisphere in coronal section showing the territories of the major cerebral vessels branching from the internal carotid arteries. (Reproduced with permission from Longo DL, Fauci AS, Kasper DL, et al. Harrison’s Principals and Practice of Internal Medicine, 18th ed. New York: McGraw-Hill, 2012.)
TREATMENT
Stroke
Desired Outcomes
The goals of treatment of acute stroke are to (a) reduce the ongoing neurologic injury and decrease mortality and long-term disability, (b) prevent complications secondary to immobility and neurologic dysfunction, and (c) prevent stroke recurrence.14 Primary prevention of stroke is reviewed elsewhere.8
General Approach to Treatment
The initial approach to the patient with a presumed acute stroke is to ensure that the patient is supported from a respiratory and cardiac standpoint and to quickly determine whether the lesion is ischemic or hemorrhagic, based on a CT scan. Ischemic stroke patients presenting within hours of the onset of their symptoms should be evaluated for reperfusion therapy. 
TIAs also require urgent intervention to reduce the risk of stroke, which is known to be highest in the first few days after TIA.15 According to the American Stroke Association guidelines, patients with elevated blood pressure should remain untreated unless their blood pressure exceeds 220/120 mm Hg, or they have evidence of aortic dissection, acute myocardial infarction (AMI), pulmonary edema, or hypertensive encephalopathy. However, this level of blood pressure may be too high, and a number of clinical trials are currently testing more aggressive treatment of hypertension in the acute setting. If blood pressure is treated, short-acting parenteral agents, such as labetalol and nicardipine, or nitroprusside, are favored. Current recommendations regarding management of arterial hypertension in stroke patients are given in Table 10-2.14 In patients with SAH, if an aneurysm is found by angiography, endovascular coiling or clipping via a craniotomy should be performed to reduce the risk of rebleeding.16 In ICH, patients may require external ventricular drainage (EVD) if there is intraventricular blood and evolving hydrocephalus (enlargement of the ventricles). Once the patient is out of the hyperacute phase, attention is placed on preventing worsening, minimizing complications, and instituting appropriate secondary prevention strategies. The acute phase of the stroke includes the first week after the event.14
TABLE 10-2 Blood Pressure Treatment Guidelines in Acute Ischemic Stroke Patients
Nonpharmacologic Therapy
Ischemic Stroke Surgical interventions in the acute ischemic stroke patient are limited. In less than 10% of patients with a large infarction in the middle cerebral artery territory, decompressive surgery to reduce intracranial pressure has been shown to significantly reduce mortality. However, the surgery must be performed within 48 hours of stroke onset to significantly improve functional outcome and this is at the cost of an increased number of surviving patients with severe disability.17 In cases of significant swelling associated with a cerebellar infarction, surgical decompression can be lifesaving. Beyond surgical intervention, however, the use of an organized, multidisciplinary approach to stroke care that includes early rehabilitation has been shown to be very effective in reducing the ultimate disability owing to ischemic stroke. In fact, the use of “stroke units” has been associated with outcomes similar to those achieved with early thrombolysis when compared with usual care.14
In secondary prevention, carotid endarterectomy of an ulcerated and/or stenotic carotid artery is a very effective way to reduce stroke incidence and recurrence in appropriate patients and in centers where the operative morbidity and mortality are low. In fact, in ischemic stroke patients with 70% to 99% stenosis of an ipsilateral internal carotid artery, recurrent stroke risk can be reduced by up to 48% compared with medical therapy alone when combined with aspirin 325 mg daily.18 In patients less than 70 years of age, carotid stenting is a less invasive alternative and can be effective in reducing recurrent stroke risk.19 However, in patients with intracranial stenosis, aggressive medical management was shown to be superior to stenting in reducing recurrent stroke.20
Hemorrhagic Stroke In patients with SAH owing to a ruptured intracranial aneurysm, in AVMs, surgical intervention to either clip or ablate the offending vascular abnormality substantially reduces mortality owing to rebleeding.16In the case of primary ICH, surgical evacuation appears to be of benefit if undertaken within 8 hours of onset and in patients with intermediate hemorrhage volumes (20 to 50 mL).12Insertion of an EVD for hydrocephalus and subsequent monitoring of intracranial pressure are done commonly and are the least invasive of the procedures done in these patients.
Pharmacologic Therapy
Ischemic Stroke
Drug Treatments of First Choice: Published Guidelines The Stroke Council of the American Stroke Association and the American College of Chest Physicians have created and published guidelines that address the management of acute ischemic stroke.7,14 For acute treatment, the only two pharmacologic agents with class I recommendations are IV tissue plasminogen activator (tPA) within 4.5 hours of onset and aspirin within 48 hours of onset.7,14
Early reperfusion (<4.5 hours from onset) with IV tPA has been shown to reduce the ultimate disability caused by ischemic stroke.21,22 Caution must be exercised when using this therapy, and adherence to a strict protocol is essential to achieving positive outcomes.14 The essentials of the treatment protocol can be summarized as (a) stroke team activation, (b) treatment as early as possible within 4.5 hours of onset, (c) CT scan to rule out hemorrhage, (d) meeting inclusion and exclusion criteria (Table 10-3), (e) administration of tPA 0.9 mg/kg over 1 hour, with 10% given as initial bolus over 1 minute, (f) avoidance of antithrombotic (anticoagulant or antiplatelet) therapy for 24 hours, and (g) close patient monitoring for elevated blood pressure, response, and hemorrhage.14
TABLE 10-3 Inclusion and Exclusion Criteria for Alteplase Use in Acute Ischemic Stroke14, 21,22
Early aspirin therapy has also been shown to reduce long-term death and disability23,24 but should never be given within 24 hours of the administration of tPA because it can increase the risk of bleeding in such patients.14
Antiplatelet therapy is the cornerstone of antithrombotic therapy for the secondary prevention of ischemic stroke and should be used in noncardioembolic strokes. Acetylsalicylic acid (ASA), clopidogrel, and extended-release dipyridamole plus aspirin (ERDP-ASA) are considered first-line antiplatelet agents.25 Cilostazol is also a recommended first-line antiplatelet agent, but its use has been limited by a lack of data in other than Asian populations.7
In patients with atrial fibrillation and a presumed cardiac source of embolism, oral anticoagulation is recommended for secondary stroke prevention.7,25 The choice of other oral anticoagulants (e.g., dabigatran) over vitamin K antagonism (warfarin) may be recommended in some patients.7 Other pharmacotherapy recommended for secondary prevention of stroke includes blood pressure lowering and statin therapy. Current recommendations regarding the acute treatment and secondary prevention of stroke are given in Table 10-4.
TABLE 10-4 Recommendations for Pharmacotherapy of Ischemic Stroke
General Information Regarding Safety and Efficacy (Including Pivotal Clinical Trials)
tPA The effectiveness of IV tPA in the treatment of ischemic stroke was first demonstrated in the National Institute of Neurologic Disorders and Stroke (NINDS) Recombinant Tissue-Type Plasminogen Activator (rtPA) Stroke Trial, published in 1995.21 In 624 patients treated in equal numbers with either tPA 0.9 mg/kg IV or placebo within 3 hours of the onset of their neurologic symptoms, 39% of the treated patients achieved an “excellent outcome” at 3 months compared with 26% of the placebo patients. An “excellent outcome” was defined as minimal or no disability by several different neurologic scales. This beneficial effect was reported despite a 10-fold increase in the risk of symptomatic ICH in the tPA-treated patients (0.6% vs. 6.4%). Overall mortality was not significantly different between the two groups (17% with tPA and 21% with placebo). Patients with very severe symptoms at baseline (National Institutes of Health Stroke Scale [NIHSS] >20) and early ischemic changes on CT scan were shown to be at highest risk for the development of symptomatic intracranial hemorrhage. Even in patients at highest risk for bleeding, however, those receiving tPA had better outcomes at 90 days than those who received placebo.21
Thirteen years after the NINDS trial, the European Cooperative Acute Stroke Study (ECASS) III demonstrated that, even when administered between 3 and 4.5 hours after the onset of symptoms, ischemic stroke patients benefit from tPA when compared with placebo (52.4% vs. 45.2% excellent outcome; P = 0.04).22 The benefit was less than that reported with earlier treatment but the rate of excess hemorrhage was similar, leading to a change in AHA guidelines to recommend extension of the window.25 An important caveat was that the exclusion criteria for later treatment are more strict and are given in Table 10-3. The International Stroke Trial (IST)-3 reported subsequently, in a large group of 3,035 patients treated within 6 hours of ischemic stroke onset, that even patients outside the rigid criteria set forth by both the NINDS and ECASS III trials may experience improved functional outcome.26 These investigators advocate that patients over the age of 80, presenting outside the 3-hour treatment window, may benefit from a personalized assessment of risk and benefit prior to excluding them from thrombolytic therapy.
ASA The use of early ASA to reduce long-term death and disability owing to ischemic stroke is supported by two large randomized clinical trials. In the IST,24 aspirin 300 mg/day significantly reduced stroke recurrence within the first 2 weeks without effect on early mortality, resulting in a significant decrease in death and dependency at 6 months. In the Chinese Acute Stroke Trial (CAST),23 aspirin 160 mg/day reduced the risk of recurrence and death in the first 28 days, but long-term death and disability were not different than with placebo. In both trials, a small but significant increase in hemorrhagic transformation of the infarction was demonstrated. Overall, the beneficial effects of early aspirin have been embraced and adopted into clinical guidelines.
Antiplatelet Agents All patients who have had an acute ischemic stroke or TIA should receive long-term antithrombotic therapy for secondary prevention.25 In patients with noncardioembolic stroke, this will be some form of antiplatelet therapy. In a comprehensive meta analysis, the overall benefit of antiplatelet therapy in patients with atherothrombotic disorders was estimated to be 22%.27 ASA is the best studied of the available agents but published literature has supported the use of clopidogrel, the combination product extended-release dipyridamole plus acetylsalicylic acid (ERDP-ASA), and cilostazol as additional first-line agents in secondary stroke prevention.7,25
The efficacy of clopidogrel as an antiplatelet agent in atherothrombotic disorders was demonstrated in the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial.28 In this study of more than 19,000 patients with a history of myocardial infarction (MI), stroke, or peripheral arterial disease (PAD), clopidogrel 75 mg/day was compared with ASA 325 mg/day for its ability to decrease MI, stroke, or cardiovascular death. In the final analysis, clopidogrel was slightly (8% relative risk reduction [RRR]) more effective than ASA (P = 0.043) and had a similar incidence of adverse effects. It is not associated with the blood dyscrasias (neutropenia) common with its congener, ticlopidine, and is used widely in patients with atherosclerosis.
In the European Stroke Prevention Study 2 (ESPS-2), ASA 25 mg and ERDP 200 mg twice daily were compared alone and in combination with placebo for their ability to reduce recurrent stroke over a 2-year period.29 In a total of more than 6,600 patients, all three treatment groups were shown to be superior to placebo—ASA alone (18% RRR), ERDP alone (16% RRR), and the combination (37% RRR). In addition, the combination demonstrated a significant advantage over the ASA-alone group (23% RRR; P = 0.006) and the ERDP-alone group (24% RRR; P = 0.002). Headache resulting in discontinuation occurred in approximately 15% of the ERDP groups (four times more common than in the placebo group), and the ASA-treated patients, even at the low dose of 50 mg/day, experienced significantly more bleeding than the other groups. The European/Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT) confirmed the results of ESPS-2, in that the combination of dipyridamole (83% extended release) and ASA (30 to 325 mg daily) was more effective than ASA alone in reducing recurrent stroke.30 Headache was again an important cause of discontinuation in the ESPRIT trial. In a large, multinational trial (Prevention Regimen for Effectively Avoiding Second Strokes [PRoFESS]) comparing ERDP-ASA with clopidogrel, the risk of recurrent stroke was similar for the two antiplatelet agents, but clopidogrel was better tolerated with less bleeding and headache.31
Cilostazol is an antiplatelet agent mostly used in the treatment of intermittent claudication. However, in a systematic assessment of two separate large randomized trials in Asian patients, cilostazol significantly reduced the risk of recurrent vascular events (RR 0.72) and hemorrhagic stroke (RR 0.26), compared with ASA.32 Despite the fact that cilostazol caused less bleeding events than ASA, there were more overall minor adverse events, including headache (21.3% vs. 13.9%) and GI disturbance (9.66% vs. 5.02%).
Oral Anticoagulants Oral anticoagulation is the treatment of choice for the prevention of stroke in patients with atrial fibrillation.7,25 In patients with atrial fibrillation and a recent history of stroke or TIA, the risk of recurrence places these patients in one of the highest risk categories known. In the European Atrial Fibrillation Trial (EAFT), 669 patients with nonvalvular atrial fibrillation (NVAF) and a prior stroke or TIA were randomized to warfarin (international normalized ratio [INR] = 2.5 to 4), ASA 300 mg/day, or placebo. Patients in the placebo group experienced stroke, MI, or vascular death at a rate of 17% per year compared with 8% per year in the warfarin group and 15% per year in the ASA group. This represents a 53% reduction in risk with anticoagulation.33 Subsequent studies in the primary prevention of stroke in patients with NVAF have demonstrated that targeting an INR of 2.5 prevents stroke with the lowest bleeding risk (Stroke Prevention in Atrial Fibrillation [SPAF III]); therefore, a target INR of 2.5 is recommended in the secondary prevention of stroke.7,25 Newer oral anticoagulants including dabigatran (direct thrombin inhibitor), rivaroxaban, and apixaban (direct factor Xa inhibitors) have significant advantages over warfarin in terms of ease of dosing and less food and drug interactions. In addition, in the prevention of stroke in selected patients with atrial fibrillation, all three agents have been shown to be as effective as, and in some cases, superior to, warfarin in reducing recurrent events and intracranial hemorrhage.34,35 For the secondary prevention of stroke in patients with atrial fibrillation, dabigatran 150 mg twice daily is recommended as either a first-line agent (ACCP) or one of several first-line oral anticoagulants.7,25 Use of warfarin in the secondary prevention of noncardioembolic stroke was addressed in the Warfarin Aspirin Recurrent Stroke Study.36 In 2,206 patients with recent stroke, warfarin (INR = 1.4 to 2.8) was not superior to ASA 325 mg/day in the prevention of recurrent events. Further data from the Warfarin–Aspirin in Intracranial Disease (WASID) trial demonstrated that ASA therapy was as effective as and safer than warfarin in patients with intracranial stenosis.37 These studies led most clinicians to abandon the practice of using warfarin in all but patients with cardioembolic sources of emboli, mainly atrial fibrillation.
Blood Pressure Lowering 
Elevated blood pressure is very common in ischemic stroke patients, and treatment of hypertension in these patients is associated with a decreased risk of stroke recurrence.38 In the Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS), a multinational stroke population (40% Asian) was randomized to receive either blood pressure lowering with the angiotensin-converting enzyme (ACE) inhibitor perindopril (with or without the thiazide diuretic indapamide) or placebo.38 Treated patients achieved an overall 9 mm Hg systolic and 4 mm Hg diastolic blood pressure reduction, and this was associated with a 28% reduction in stroke recurrence. In the patients who received the combination treatment (clinician’s discretion), the average blood pressure lowering achieved was 12 mm Hg systolic and 5 mm Hg diastolic, and this was associated with an even larger reduction in stroke recurrence (43%). Similar results were achieved in patients with and without hypertension. AHA/ASA guidelines recommend reduction of blood pressure in patients with stroke or TIA.25 
Early blood pressure lowering can worsen symptoms, however; therefore, recommendations are limited to patients outside of the acute stroke period (first 7 days).25
Statins The statins have been shown to reduce the risk of stroke by approximately 30% in patients with coronary artery disease and elevated plasma lipids.39 The Stroke Prevention by Aggressive Reduction in Cholesterol (SPARCL) study demonstrated that atorvastatin 80 mg daily reduced the risk of recurrent stroke by 16% and coronary events by 42% in patients with no cardiac history. Although the high-dose statin caused an increase in liver enzymes, there was no increase in myopathy.40 It is now recommended that ischemic stroke patients, regardless of baseline cholesterol, be treated with high-intensity statin therapy to achieve a reduction of low-density lipoprotein (LDL) of at least 50% for secondary stroke prevention.25
Heparin for Prophylaxis of Deep Vein Thrombosis (DVT) The use of low-molecular-weight heparins or low-dose subcutaneous unfractionated heparin (5,000 units three times daily) can be recommended for the prevention of DVT in hospitalized patients with decreased mobility owing to their stroke and should be used in all but the most minor strokes.11
Alternative Drug Treatments
ASA Plus Clopidogrel In the Management of ATherothrombosis with Clopidogrel in High-risk patients (MATCH) study, clopidogrel in combination with ASA 75 mg daily was no better than clopidogrel alone in secondary stroke prevention.41 Also, when clopidogrel was used with ASA, the risk of life-threatening bleeding increased from 1.3% to 2.6%.41 Again, in the Stroke Prevention in Subcortical Stroke (SPS)-3 trial of patients with recent minor strokes, the arm of the trial studying the combination of clopidogrel and ASA was stopped early due to excess mortality due to bleeding in this group.42 However, the combination has been studied in patients with acute coronary syndromes and patients undergoing percutaneous coronary interventions and shown to be significantly more effective than ASA alone in reducing MI, stroke, and cardiovascular death.43,44 Also, in patients with high-grade intracranial stenosis, short-term (3-month) use of the combination of clopidogrel and ASA was associated with better-than-expected outcome in the aggressive medical therapy group.20 This combination should only be used in selected patients with a recent MI history or intracranial stenosis and only with ultra–low-dose ASA to minimize bleeding risk.45
Heparins The use of full-dose unfractionated heparin in the acute stroke period has never been proven to positively affect stroke outcome, and it significantly increases the risk of ICH.7,14 Trials of low-molecular-weight heparins or heparinoids have been largely negative and do not support their routine use in stroke patients.46–48 Other potential but unproven uses for treatment doses of either unfractionated or low-molecular-weight heparins include bridge therapy in patients being initiated on warfarin, carotid dissection, or continuous worsening of ischemia despite adequate antiplatelet therapy.7
Drug Class Information
ASA ASA exerts its antiplatelet effect by irreversibly inhibiting cyclooxygenase, which, in platelets, prevents conversion of arachidonic acid to thromboxane A2 (TXA2), which is a powerful vasoconstrictor and stimulator of platelet aggregation. Platelets remain impaired for their life span (5 to 7 days) after exposure to aspirin. ASA also inhibits prostacyclin (PGI2) activity in the smooth muscle of vascular walls. PGI2 inhibits platelet aggregation, and the vascular endothelium can synthesize PGI2 such that the platelet antiaggregating effect is maintained.7 There is probably a point at which lower doses of ASA do not completely block TXA2, and recent studies indicate that the lowest effective dose may be in the range of 50 mg/day.49 Upper GI discomfort and bleeding are the most common adverse effects of ASA and have been shown to be dose related. The highest rates of GI bleeding (5%) have been reported in patients receiving 1,200 mg/day as compared with rates of 2% in patients taking the more commonly prescribed 300 mg/day. Upper GI symptoms are much more common than frank bleeding, however, with 40% of patients affected at 1,200 mg/day and 25% at 300 mg/day.50 In the ESPS-2 study, even 50 mg/day of ASA was associated with a twofold increase in bleeding over the placebo group.29
The onset of the antiplatelet effect of ASA is less than 60 minutes.51 It has been reported, however, that some patients either have or develop “aspirin resistance” and can require higher doses to achieve the desired antiplatelet effect.52 Despite this, routine testing for ASA resistance is not recommended. It was observed that administration of ibuprofen prior to the administration of a daily aspirin dose inhibits the ASA from binding irreversibly to the cyclooxygenase and can decrease its antiplatelet effect.53 Current recommendations are to administer ASA at least 2 hours before ibuprofen or to wait at least 4 hours after an ibuprofen dose.
Clopidogrel Clopidogrel has a unique platelet antiaggregatory effect in that it is an inhibitor of the adenosine diphosphate (ADP) pathway of platelet aggregation and inhibits known stimuli to platelet aggregation.7,28 This effect causes an alteration of the platelet membrane and interference with the membrane–fibrinogenic interaction leading to a blocking of the platelet glycoprotein IIb/IIIa receptor. A time lag of 3 to 7 days before the antiplatelet effect is maximal should be expected. The tolerability of clopidogrel 75 mg/day is at least as good as medium-dose (325 mg/day) ASA, and there is less GI bleeding.28Clopidogrel is associated with an increased risk of diarrhea and rash, but discontinuation rates owing to adverse effects are similar to those with ASA 325 mg/day (5.3% and 6%, respectively).28 There is no excess neutropenia in patients taking clopidogrel, and rates of thrombotic thrombocytopenic purpura probably are no greater than background rate.
Extended-Release Dipyridamole Plus ASA Early studies of the role of dipyridamole in stroke prevention failed to show a benefit over that realized by ASA alone. Dipyridamole in high doses is thought to inhibit platelet aggregation by inhibiting phosphodiesterase, leading to accumulation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) intracellularly, which prevent platelet activation. In addition, dipyridamole also enhances the antithrombotic potential of the vascular wall.54 The ESPS-2 demonstrated the efficacy of high-dose ERDP alone and in combination with ASA in secondary stroke prevention.29 The extended-release formulation of dipyridamole is important in that it allows twice-daily administration and higher doses to be tolerated in patients. The use of immediate-release generic dipyridamole in combination with regular ASA, in order to reduce costs, is unproven and should be discouraged.
In the ESPS-2, 25% of the patients who received combination dipyridamole and ASA discontinued the therapy early, and the rate of discontinuation owing to headache was more than three times as common (10%) as in the aspirin-alone group (3%).29 Even when patients were carefully educated and coached in the PRoFESS trial, discontinuation due to headache was six times higher in the ERDP-ASA group (5.9% vs. 0.9%).31
Investigational Strategies
Reperfusion Various investigations aimed at opening the occluded cerebral artery and preserving its patency are under way in acute ischemic stroke patients.55 Strategies being tried include longer-acting fibrinolytic agents, intraarterial fibrinolysis with tPA and other agents, and endovascular clot removal using mechanical and laser-guided approaches. Although the endovascular devices are used extensively in some centers, expert guidelines recommend against their routine use.7 In addition, investigators are trying to identify, using sensitive MRI techniques, which patients benefit from reperfusion at time points outside the approved time window. Undoubtedly, efforts to reperfuse the ischemic brain will continue to be explored, so more patients will be eligible for this therapy.
Neuroprotection and Neurorestoration Although many different neuroprotective agents have been studied in clinical trials of acute ischemic stroke, all have been unsuccessful.55 Magnesium and albumin are still under investigation, but the drug development pipeline for acute neuroprotection is essentially nonexistent. However, hope exists that clinicians will be able to enhance the reparative process of the brain (neurorestoration) through targeted neurorehabilitation, growth factor enhancement, and the use of neural and cell transplantation.55
A promising nonpharmacologic strategy that has been shown to provide neuroprotection in patients has been hypothermia.56 There remains uncertainty on the best way to optimize the mechanism of cooling the ischemic brain (intravascular coils vs. surface cooling) and rewarming the patient after hypothermia.
Hemorrhagic Stroke
There are currently no standard pharmacologic strategies for treating ICH.11 Medical guidelines for the management of blood pressure, raised intracranial pressure, and other medical complications of ICH are those required for the management of any acutely ill patient in a neurointensive care unit.11 When ICH occurs in a patient on oral anticoagulants, reversal of anticoagulation to prevent expansion and allow surgical intervention is recommended. The methods recommended to achieve reversal include IV vitamin K, fresh-frozen plasma (FFP), and hemostatic agents (factor VIIa and prothrombin complex concentrate [PCC]).11 The optimal approach, particularly in patients on the newer oral anticoagulants, is yet to be determined.
SAH owing to aneurysm rupture is associated with a high incidence of delayed cerebral ischemia (DCI) in the 2 weeks following the bleeding episode. Vasospasm of the cerebral vasculature is thought to be responsible for DCI and occurs between 4 and 21 days after the bleed, peaking at days 5 to 9.16 The calcium channel blocker nimodipine (60 mg every 4 hours for 21 days), along with maintenance of intravascular volume with pressor therapy, is recommended to reduce the incidence and severity of neurologic deficits owing to DCI.16
PERSONALIZED PHARMACOTHERAPY
Clopidogrel is a thienopyridine prodrug and needs to be biotransformed by the liver to an active metabolite. Evidence suggests that the antiplatelet effects of clopidogrel can be diminished in patients with reduced-function cytochrome P450 2C19 (CYP2C19)57 or in those receiving agents that inhibit hepatic metabolism.58 In patients receiving clopidogrel after stent placement, reduced-function CYP2C19 is associated with an increase in recurrent vascular events.58 Although high doses of the lipophilic statins atorvastatin and simvastatin can diminish the effectiveness of clopidogrel to inhibit platelet aggregation in vitro, there does not appear to be any adverse effect on atherothrombotic event rates.59 In contrast, in a retrospective analysis of 8,205 patients, concomitant proton pump inhibitor and clopidogrel treatment was associated with increased adverse vascular outcomes after acute coronary syndromes.57 Careful consideration should be given to using clopidogrel in patients with reduced ability to biotransform the agent to its active metabolite.
The availability of genetic testing to identify patients with altered sensitivity to warfarin has led to questions regarding the ability of the tests to improve patient care. Polymorphisms in CYP2C9 and vitamin K epoxide reductase complex subunit 1 (VKORC1) contribute to the variability in warfarin response, but it is unclear whether knowledge of these genetic variations will improve dosing accuracy and reduce adverse events.60 Clinical trial evidence is needed prior to instituting these tests in stroke patients who are candidates for warfarin therapy.
EVALUATION OF THERAPEUTIC OUTCOMES
Monitoring of the Pharmaceutical Care Plan
Patients with acute stroke should be monitored intensely for the development of neurologic worsening (recurrence or extension), complications (thromboembolism or infection), or adverse effects from pharmacologic or nonpharmacologic interventions. The most common reasons for deterioration in a stroke patient are (a) extension of the original lesion—ischemic or hemorrhagic—in the brain, (b) development of cerebral edema and raised intracranial pressure, (c) hypertensive emergency, (d) infection (urinary and respiratory most common), (e) venous thromboembolism (DVT and pulmonary embolism), (f) electrolyte abnormalities and cardiac rhythm disturbances (can be associated with brain injury), and (g) recurrent stroke.
The approach to monitoring drug therapy in the hospitalized stroke patient is summarized in Table 10-5. The plan should be customized for individual patients based on their comorbidities and ongoing disease processes.
TABLE 10-5 Monitoring Stroke Therapy
Clinical Controversy…
Rapid reversal of the INR with hemostatic agents in patients with oral anticoagulant–associated intracranial hemorrhage may reduce the risk of extension of the lesion but also carries a risk of thromboembolic events. The correct approach to management of this adverse effect of anticoagulant therapy is unknown.
Aggressive BP lowering in patients with intracranial hemorrhage may reduce the risk of hemorrhage extension. Although this practice may be safe, it is unclear whether it can improve outcome.
ABBREVIATIONS
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