ischaemia

Ischemic Stroke

Ischemic stroke is sudden neurologic deficits that result from focal cerebral ischemia associated with permanent brain infarction (eg, positive results on diffusion-weighted MRI). Common causes are (from most to least common) atherothrombotic occlusion of large arteries; cerebral embolism (embolic infarction); nonthrombotic occlusion of small, deep cerebral arteries (lacunar infarction); and proximal arterial stenosis with hypotension that decreases cerebral blood flow in arterial watershed zones (hemodynamic stroke). Diagnosis is clinical, but CT or MRI is done to exclude hemorrhage and confirm the presence and extent of stroke. Thrombolytic therapy may be useful acutely in certain patients. Depending on the cause of stroke, carotid endarterectomy or stenting, antiplatelet drugs, or warfarin may help reduce risk of subsequent strokes.

Etiology of Ischemic Stroke

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The following are the modifiable risk factors that contribute the most to increased risk of ischemic stroke:

Hypertension
Cigarette smoking
Dyslipidemia
Diabetes
Insulin resistance ( 1)
Abdominal obesity
Excess alcohol consumption
Lack of physical activity
High-risk diet (eg, high in saturated fats, trans fats, and calories)
Psychosocial stress (eg, depression)
Heart disorders (particularly disorders that predispose to emboli, such as acute myocardial infarction, infective endocarditis, and atrial fibrillation)
Use of certain drugs (eg, cocaine, amphetamines)
Hypercoagulability
Vasculitis
Use of exogenous estrogen

Unmodifiable risk factors include the following:

Prior stroke
Sex
Race/ethnicity
Older age
Family history of stroke

The most common causes of ischemic stroke can be classified as

Cryptogenic (ie, no clear cardioembolic, lacunar, or atherosclerotic source; the most common classification)
Cardioembolism
Lacunar infarcts
Large-vessel atherosclerosis (the 4th most common cause)

Large-vessel atherosclerosis

Large-vessel atherosclerosis can affect intracranial or extracranial arteries.

Atheromas, particularly if ulcerated, predispose to thrombi. Atheromas can occur in any major cerebral artery and are common at areas of turbulent flow, particularly at the carotid bifurcation. Partial or complete thrombotic occlusion occurs most often at the main trunk of the middle cerebral artery and its branches but is also common in the large arteries at the base of the brain, in deep perforating arteries, and in small cortical branches. The basilar artery and the segment of the internal carotid artery between the cavernous sinus and supraclinoid process are often occluded.

Cardioembolism

Emboli may lodge anywhere in the cerebral arterial tree.

Emboli may originate as cardiac thrombi, especially in the following conditions:

Atrial fibrillation
Rheumatic heart disease (usually mitral stenosis)
Post–myocardial infarction
Vegetations on heart valves in bacterial or marantic endocarditis
Prosthetic heart valves
Mechanical circulatory assist devices (eg, left ventricular assist device, or LVAD [ 2])

Other sources include clots that form after open-heart surgery and atheromas in neck arteries or in the aortic arch. Rarely, emboli consist of fat (from fractured long bones), air (in decompression sickness), or venous clots that pass from the right to the left side of the heart through a patent foramen ovale with shunt (paradoxical emboli). Emboli may dislodge spontaneously or after invasive cardiovascular procedures (eg, catheterization). Rarely, thrombosis of the subclavian artery results in embolic stroke in the vertebral artery or its branches.

Lacunar infarcts

Ischemic stroke can also result from lacunar infarcts. These small (≤ 1.5 cm) infarcts result from nonatherothrombotic obstruction of small, perforating arteries that supply deep cortical structures; the usual cause is lipohyalinosis (degeneration of the media of small arteries and replacement by lipids and collagen). Whether emboli cause lacunar infarcts is controversial.

Lacunar infarcts tend to occur in older patients with diabetes or poorly controlled hypertension.

Other causes

Less common causes of stroke include vascular inflammation secondary to disorders such as acute or chronic meningitis, vasculitic disorders, and syphilis; dissection of intracranial arteries or the aorta; hypercoagulability disorders (eg, antiphospholipid syndrome, hyperhomocysteinemia); hyperviscosity disorders (eg, polycythemia, thrombocytosis, hemoglobinopathies, plasma cell disorders); and rare disorders (eg, fibromuscular dysplasia, moyamoya disease, Binswanger disease).

In children, sickle cell disease is a common cause of ischemic stroke.

Any factor that impairs systemic perfusion (eg, carbon monoxide toxicity, severe anemia or hypoxia, polycythemia, hypotension) increases risk of all types of ischemic strokes. A stroke may occur along the borders between territories of arteries (watershed areas); in such areas, blood supply is normally low, particularly if patients have hypotension and/or if major cerebral arteries are stenotic.

Less commonly, ischemic stroke results from vasospasm (eg, during migraine, after subarachnoid hemorrhage, after use of sympathomimetic drugs such as cocaine or amphetamines) or venous sinus thrombosis (eg, during intracranial infection, postoperatively, peripartum, secondary to a hypercoagulability disorder).

Etiology references

1. Kernan WN, Viscoli CM, Furie KL, et al: Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 374 (14):1321–1331, 2016. doi: 10.1056/NEJMoa1506930.
2. Morgan JA, Brewer RJ, Nemeh HW, et al: Stroke while on long-term left ventricular assist device support: incidence, outcome, and predictors. ASAIO J 60 (3):284–289, 2014. doi: 10.1097/MAT.0000000000000074.

Pathophysiology of Ischemic Stroke

Inadequate blood flow in a single brain artery can often be compensated for by an efficient collateral system, particularly between the carotid and vertebral arteries via anastomoses at the circle of Willis and, to a lesser extent, between major arteries supplying the cerebral hemispheres. However, normal variations in the circle of Willis and in the caliber of various collateral vessels, atherosclerosis, and other acquired arterial lesions can interfere with collateral flow, increasing the chance that blockage of one artery will cause brain ischemia.

Some neurons die when perfusion is < 5% of normal for > 5 minutes; however, the extent of damage depends on the severity of ischemia. If it is mild, damage proceeds slowly; thus, even if perfusion is 40% of normal, 3 to 6 hours may elapse before brain tissue is completely lost. However, if severe ischemia persists > 15 to 30 minutes, all of the affected tissue dies (infarction). Damage occurs more rapidly during hyperthermia and more slowly during hypothermia. If tissues are ischemic but not yet irreversibly damaged, promptly restoring blood flow may reduce or reverse injury. For example, intervention may be able to salvage the moderately ischemic areas (penumbras) that often surround areas of severe ischemia; penumbras exist because of collateral flow.

Mechanisms of ischemic injury include

Edema
Microvascular thrombosis
Programmed cell death (apoptosis)
Infarction with cell necrosis

Inflammatory mediators (eg, interleukin-1B, tumor necrosis factor-alpha) contribute to edema and microvascular thrombosis. Edema, if severe or extensive, can increase intracranial pressure.

Many factors may contribute to necrotic cell death; they include loss of adenosine triphosphate (ATP) stores, loss of ionic homeostasis (including intracellular calcium accumulation), lipid peroxidative damage to cell membranes by free radicals (an iron-mediated process), excitatory neurotoxins (eg, glutamate), and intracellular acidosis due to accumulation of lactate.

Symptoms and Signs of Ischemic Stroke

Symptoms and signs of ischemic stroke depend on the part of brain affected. Patterns of neurologic deficits often suggest the affected artery (see table Selected Stroke Syndromes), but correlation is often inexact.

Selected Stroke Syndromes

Deficits may become maximal within several minutes of onset, typically in embolic stroke. Less often, deficits evolve slowly, usually over 24 to 48 hours (called evolving stroke or stroke in evolution), typically in atherothrombotic stroke.

In most evolving strokes, unilateral neurologic dysfunction (often beginning in one arm, then spreading ipsilaterally) extends without causing headache, pain, or fever. Progression is usually stepwise, interrupted by periods of stability.

A stroke is considered submaximal when after it is complete, there is residual function in the affected area, suggesting viable tissue at risk of damage.

Embolic strokes often occur during the day; headache may precede neurologic deficits. Thrombi tend to occur during the night and thus are first noticed on awakening.

Lacunar infarcts may produce one of the classic lacunar syndromes (eg, pure motor hemiparesis, pure sensory hemianesthesia, ataxic hemiparesis, dysarthria–clumsy hand syndrome); signs of cortical dysfunction (eg, aphasia) are absent. Multiple lacunar infarcts may result in multi-infarct dementia.

A seizure may occur at stroke onset, more often with embolic than thrombotic stroke. Seizures may also occur months to years later; late seizures result from scarring or hemosiderin deposition at the site of ischemia.

Deterioration during the first 48 to 72 hours after onset of symptoms, particularly progressively impaired consciousness, results more often from cerebral edema than from extension of the infarct. Unless the infarct is large or extensive, function commonly improves within the first few days; further improvement occurs gradually for up to 1 year.

Diagnosis of Ischemic Stroke

Primarily clinical evaluation
Neuroimaging and bedside glucose testing
Evaluation to identify the cause

Diagnosis of ischemic stroke is suggested by sudden neurologic deficits referable to a specific arterial territory. Ischemic stroke must be distinguished from other causes of similar focal deficits (sometimes called stroke mimics), such as

Hypoglycemia
Postictal [Todd] paralysis (a transient neurologic deficit, usually weakness, of the limb contralateral to the seizure focus)
Hemorrhagic stroke
Rarely, migraine

Headache, coma or stupor, and vomiting are more likely with hemorrhagic stroke.

Evaluation of ischemic stroke requires assessment of the brain parenchyma, vascular system (including the heart and large arteries), and blood.

Differentiating clinically between the types of stroke is imprecise; however, some clues based on symptom progression, time of onset, and type of deficit can help.

Although diagnosis is clinical, neuroimaging and bedside glucose testing are mandatory.

Distinction between lacunar, embolic, and thrombotic stroke based on history, examination, and neuroimaging is not always reliable, so tests to identify common or treatable causes and risk factors for all of these types of strokes are routinely done. Patients should be evaluated for the following categories of causes and risk factors:

Cardiac (eg, atrial fibrillation, potential structural sources of emboli)
Vascular (eg, critical arterial stenosis)
Blood (eg, hypercoagulability)

A cause cannot be identified for some strokes (cryptogenic strokes).

Brain assessment

Neuroimaging with CT or MRI is done first to exclude intracerebral hemorrhage, subdural or epidural hematoma, and a rapidly growing, bleeding, or suddenly symptomatic tumor. CT evidence of even a large anterior circulation ischemic stroke may be subtle during the first few hours; changes may include effacement of sulci or the insular cortical ribbon, loss of the gray-white junction between cortex and white matter, and a dense middle cerebral artery sign. Within 6 to 12 hours of ischemia, medium-sized to large infarcts start to become visible as hypodensities; small infarcts (eg, lacunar infarcts) may be visible only with MRI.

Diffusion-weighted MRI (highly sensitive for early ischemia) can be done immediately after initial CT neuroimaging.

Cardiac causes

For cardiac causes, testing typically includes ECG, telemetry or Holter monitoring, serum troponin, and transthoracic or transesophageal echocardiography.

Vascular causes

For vascular causes, testing may include magnetic resonance angiography (MRA), CT angiography (CTA), carotid and transcranial duplex ultrasonography, and conventional angiography. The choice and sequence of testing is individualized, based on clinical findings. MRA, CTA, and carotid ultrasonography all show the anterior circulation; however, MRA and CTA provide better images of the posterior circulation than carotid ultrasonography. MRA is generally preferred to CTA if patients can remain still during MRA (to avoid motion artifact). Usually, CTA or MRA should be done urgently but should not delay IV tPA if it is indicated.

Effects of Thrombectomy After Stroke (Arteriogram)

IMAGE COURTESY OF JI Y. CHONG, MD.

Blood-related causes

For blood-related causes (eg, thrombotic disorders), blood tests are done to assess their contribution and that of other causes. Routine testing typically includes complete blood count (CBC), platelet count, prothrombin time/partial thromboplastin time (PT/PTT), fasting blood glucose, and lipid profile.

Depending on which causes are clinically suspected, additional tests may include measurement of homocysteine, testing for thrombotic disorders (antiphospholipid antibodies, protein S, protein C, antithrombin III, factor V Leiden), testing for rheumatic disorders (eg, antinuclear antibodies, rheumatoid factor, erythrocyte sedimentation rate), syphilis serologic testing, hemoglobin electrophoresis, and a urine drug screen for cocaine and amphetamines.

Prognosis for Ischemic Stroke

Stroke severity and progression are often assessed using standardized measures such as the National Institutes of Health (NIH) Stroke Scale (see table The National Institutes of Health Stroke Scale); the score on this scale correlates with extent of functional impairment and prognosis. During the first days, progression and outcome can be difficult to predict. Older age, impaired consciousness, aphasia, and brain stem signs suggest a poor prognosis. Early improvement and younger age suggest a favorable prognosis.

About 50% of patients with moderate or severe hemiplegia and most with milder deficits have a clear sensorium and eventually can take care of their basic needs and walk adequately. Complete neurologic recovery occurs in about 10%. Use of the affected limb is usually limited, and most deficits that remain after 12 months are permanent. Patients who have had a stroke are at high risk of subsequent strokes

Treatment of Ischemic Stroke

General stroke treatments
Acute antihypertensive therapy only in certain circumstances
Antiplatelet therapy
For acute treatment, sometimes reperfusion with recombinant tissue plasminogen activator (IV or thrombolysis-in-situ), and/or mechanical thrombectomy
Sometimes anticoagulation
Long-term control of risk factors
Sometimes carotid endarterectomy or stenting

Acute stroke treatment

Guidelines for early management of stroke are available from the American Heart Association and American Stroke Association. Patients with acute ischemic strokes are usually hospitalized.

Supportive measures such as the following may be needed during initial evaluation and stabilization.

Airway support and ventilatory assistance if decreased consciousness or bulbar dysfunction compromises the airway
Supplemental oxygen only if needed to maintain oxygen saturation > 94%
Correction of hyperthermia (temperature > 38° C) by using an antipyretic drug and identifying and treating the cause of hypothermia
Treatment of hypoglycemia (blood glucose < 60 mg/dL)
Treatment of hyperglycemia (a reasonable option) to lower blood glucose to 140 to 180 mg/dL while closely monitoring for hypoglycemia

Perfusion of an ischemic brain area may require a high blood pressure (BP) because autoregulation is lost; thus, BP should not be decreased except in the following cases:

There are signs of other end-organ damage (eg, aortic dissection, acute myocardial infarction, pulmonary edema, hypertensive encephalopathy, retinal hemorrhages, acute renal failure).
Use of recombinant tissue plasminogen activator (tPA) and/or mechanical thrombectomy is likely.

If BP is ≥ 220 mm Hg systolic or ≥ 120 mm Hg diastolic on 2 successive readings 15 minutes apart, lowering BP by 15% in the 24 hours after stroke onset is reasonable.

For patients who are eligible for acute reperfusion therapy except that BP is > 185/110 mm Hg, BP can be treated to decrease BP to below > 185/110 mm Hg0 t with one of the following:

Labetalol 10 to 20 mg IV bolus over 1 to 2 minutes (may repeat 1 time)
Nicardipine 5 mg/hour IV infusion initially (dose is increased by 2.5 mg/hour every 5 to 15 minutes to a maximum of 15 mg/hour)
Clevidipine 1 to 2 mg/hour IV infusion (titrate by doubling the dose every 2 to 5 minutes until desired BP is reached to a maximum of 21 mg/hour)

Patients with presumed thrombi or emboli may be treated with one or a combination of the following:

tPA, thrombolysis-in-situ, and/or mechanical thrombectomy
Antiplatelet drugs
Anticoagulants

Most patients are not candidates for thrombolytic therapy; they should be given an antiplatelet drug (usually aspirin 325 mg orally) when they are admitted to the hospital. Contraindications to antiplatelet drugs include aspirin-induced or nonsteroidal anti-inflammatory drug (NSAID)-induced asthma or urticaria, other hypersensitivity to aspirin or to tartrazine, acute gastrointestinal bleeding, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and use of warfarin.

Recombinant tPA (alteplase) can be used for patients with acute ischemic stroke up to 3 hours after symptom onset if they have no contraindications to tPA (see table Exclusion Criteria for Use of Tissue Plasminogen Activator in Stroke). Some experts recommend using tPA up to 4.5 hours after symptom onset (see Expansion of the Time Window for Treatment of Acute Ischemic Stroke With Intravenous Tissue Plasminogen Activator); however, between 3 hours and 4.5 hours after symptom onset, additional exclusion criteria apply (see table Exclusion Criteria for Use of Tissue Plasminogen Activator in Stroke).

Although tPA can cause fatal or other symptomatic brain hemorrhage, patients treated with tPA strictly according to protocols still have a higher likelihood of functional neurologic recovery. Only physicians experienced in stroke management should use tPA to treat patients with acute stroke; inexperienced physicians are more likely to violate protocols, resulting in more brain hemorrhages and deaths. When tPA is given incorrectly (eg, when given despite the presence of exclusion criteria), risk of hemorrhage due to tPA is high mainly for patients who have had stroke; risk of brain hemorrhage is very low (about 0.5%; 95% confidence interval of 0 to 2.0% [ 1]) for patients who have had a stroke mimic. If experienced physicians are not available on site, consultation with an expert at a stroke center (including video evaluation of the patient [telemedicine]), if possible, may enable these physicians to use tPA. Because most poor outcomes result from failure to strictly adhere to the protocol, a checklist of inclusion and exclusion criteria should be used.

tPA must be given within 4.5 hours of symptom onset—a difficult requirement. Because the precise time of symptom onset may not be known, clinicians must start timing from the moment the patient was last observed to be well.

Before treatment with tPA, the following are required:

Brain hemorrhage must be excluded by CT
Systolic BP must be < 185 mm Hg
Diastolic BP must be < 110 mm Hg
Blood glucose must be > 50 mg/dL

Antihypertensive drugs (IV nicardipine, IV labetalol, IV clevidipine) may be given as above. Blood pressure should be kept < 180/105 mm Hg for at least 24 hours after treatment with tPA.

Dose of tPA is 0.9 mg/kg IV (maximum dose 90 mg); 10% is given by rapid IV injection over 1 minute, and the remainder by constant infusion over 60 minutes. Vital signs are closely monitored for 24 hours after treatment. Any bleeding complications are aggressively managed. Anticoagulants and antiplatelet drugs are not used within 24 hours of treatment with tPA.

TABLE

Exclusion Criteria for Use of Tissue Plasminogen Activator in Stroke

Thrombolysis-in-situ (angiographically directed intra-arterial thrombolysis) of a thrombus or embolus can sometimes be used for major strokes if symptoms began < 6 hours ago, particularly for strokes that are due to large occlusions in the middle cerebral artery and cannot be treated with IV recombinant tPA. Clots in the basilar artery may be intra-arterially lysed up to 12 hours after stroke onset, sometimes even later depending on the clinical circumstances. This treatment, although standard of care in some large stroke centers, is often unavailable in other hospitals.

Mechanical thrombectomy (angiographically directed intra-arterial removal of a thrombus or embolus by a stent retriever device) is standard of care in large stroke centers for patients with recent large-vessel occlusion in the anterior circulation. It should not be used instead of IV recombinant tPA within 4.5 hours of onset of symptoms in eligible patients with acute ischemic stroke. Devices used to remove thrombi are being improved, and recent models reestablish perfusion in 90 to 100% of patients.

Mechanical thrombectomy can be used to treat patients who have had a severe stroke and have an NIH stroke score ≥ 6. However, recent trials have shown benefit in patients with NIH stroke scores of ≥ 2 ( 3) or even any NIH stroke score ( 4), and thus thrombectomy (or thrombolysis) is indicated.

Mechanical thrombectomy had previously been restricted to patients within 6 hours of symptom onset in patients with internal carotid artery or middle cerebral artery occlusion. However, at comprehensive stroke centers, clinical and/or imaging findings that suggest a substantial amount of tissue at risk for infarction (penumbra) may justify later treatment. For example, the volume of infarcted tissue and at-risk underperfused tissue (the ischemic penumbra) can be identified using CT perfusion or MR perfusion imaging. A sizeable mismatch between the infarct volume identified by diffusion-weighted and perfusion-weighted imaging suggests substantial penumbra that is still potentially salvageable. In the DEFUSE 3 trial, benefit was evident up to 16 hours after symptom onset in patients with a small infarct and a larger penumbra, both based on imaging criteria ( 5). In the DAWN trial, benefit was evident up to 24 hours after symptom onset in patients with a large mismatch between infarct volume based on imaging and severity of the clinical deficit based on clinical criteria ( 6); this finding suggests that salvageable penumbra is present.

Oral antiplatelet drugs are used in acute stroke treatment. The following may be used:

Aspirin 100 to 325 mg within 48 hours of stroke onset
Dual antiplatelet therapy: Aspirin plus clopidogrel (eg, 300 to 600 mg orally once, then 75 mg orally once a day) within 24 hours of stroke onset for patients at high risk of a transient ischemic attack (TIA, ABCD2 score ≥ 4) or minor stroke

Aspirin given within 48 hours reduces the risk of early recurrent stroke and death ( 7).

The ABCD2 score is calculated by adding the following

A (age): ≥ 60 = 1
B (blood pressure): Systolic blood pressure ≥ 140 and/or diastolic blood pressure > 90 = 1
C (clinical features): Weakness = 2, speech disturbance without weakness = 1
D (TIA duration): ≥ 60 min = 2, 10 to 59 min = 1, < 10 minutes = 0
D2 (diabetes) = 1

Risk of stroke within 2 days based on the ABCD2 score is about

For a score of 6 to 7: 8%
For a score of 4 to 5: 4%
For a score of 0 to 3: 1%

If patients have had a TIA or minor stroke, clopidogrel plus aspirin given within 24 hours of symptom onset and continued for 21 days appears more effective than aspirin alone for reducing risk of stroke in the first 90 days and does not increase risk of hemorrhage ( 8). However, prolonged (eg, > 3 months) use of clopidogrel plus aspirin is avoided because it has no advantage over aspirin alone in long-term secondary stroke prevention and results in more bleeding complications.

Anticoagulation with heparin or low molecular weight heparin is used for stroke caused by cerebral venous thrombosis and sometimes for stroke caused by cervical artery dissection. Anticoagulation can also be used in patients at high risk of recurrent cardiac emboli (eg, those with cardiac thrombi or mechanical valves).

Usually, anticoagulation is avoided in the acute stage because risk of hemorrhage (hemorrhagic transformation) is higher, especially with large infarcts.

Long-term stroke treatment

Supportive care is continued during convalescence:

Controlling hyperglycemia and fever can limit brain damage after stroke, leading to better functional outcomes.
Screening for dysphagia before patients begin eating, drinking, or receiving oral drugs can help identify patients at increased risk of aspiration; it should be done by a speech-language pathologist or other trained health care practitioner.
Enteral nutrition if needed should be started within 7 days of admission after an acute stoke.
Intermittent pneumatic compression (IPC) for deep venous thrombosis prophylaxis is recommended for immobile stroke patients without contraindications.
Low molecular weight heparin may be given to immobile stroke patients without contraindications.
Measures to prevent pressure ulcers are started early.

Long-term management also focuses on prevention of recurrent stroke (secondary prevention). Modifiable risk factors (eg, hypertension, diabetes, smoking, alcoholism, dyslipidemia, obesity) are treated. Reducing systolic BP may be more effective when the target BP is < 120 mm Hg rather than the typical level (< 140 mm Hg).

Extracranial carotid endarterectomy or stenting is indicated for patients with recent nondisabling, submaximal stroke attributed to an ipsilateral carotid obstruction of 70 to 99% of the arterial lumen or to an ulcerated plaque if life expectancy is at least 5 years. In other symptomatic patients (eg, patients with TIAs), endarterectomy or stenting with antiplatelet therapy is indicated for carotid obstruction of ≥ 60% with or without ulceration if life expectancy is at least 5 years. These procedures should be done by surgeons and interventionists who have a successful record with the procedure (ie, morbidity and mortality rate of < 3%) in the hospital where it will be done. If carotid stenosis is asymptomatic, endarterectomy or stenting is beneficial only when done by very experienced surgeons or interventionists, and that benefit is likely to be small. For many patients, carotid stenting with an emboli-protection device (a type of filter) is preferred to endarterectomy, particularly if patients are < 70 years and have a high surgical risk. Carotid endarterectomy and stenting are equally effective for stroke prevention. In the periprocedural period, myocardial infarction is more likely after endarterectomy, and recurrent stroke is more likely after stenting.

Extracranial vertebral angioplasty and/or stenting can be used in certain patients with recurrent symptoms of vertebrobasilar ischemia despite optimal medical treatment and a vertebral artery obstruction of 50 to 99%.

Intracranial major artery angioplasty and/or stenting is considered investigational for patients with recurrent stroke or TIA symptoms despite optimal medical treatment and a 50 to 99% obstruction of a major intracranial artery.

Endovascular closure of a patent foramen ovale does not appear to be more effective for preventing strokes than medical management, but studies are ongoing.

Oral antiplatelet drugs are used to prevent subsequent noncardioembolic (atherothrombotic, lacunar, cryptogenic) strokes (secondary prevention). The following may be used:

Aspirin 81 or 325 mg once a day
Clopidogrel 75 mg once a day
The combination product aspirin 25 mg/extended-release dipyridamole 200 mg 2 times a day

In patients taking warfarin, antiplatelet drugs additively increase risk of bleeding and are thus usually avoided; however, aspirin is occasionally used simultaneously with warfarin in certain high-risk patients. Clopidogrel is indicated for patients who are allergic to aspirin. If ischemic stroke recurs or if a coronary artery stent becomes blocked while patients are taking clopidogrel, clinicians should suspect impaired metabolism of clopidogrel (ineffective conversion of clopidogrel to its active form because cytochrome P-450 2C19 [CYP2C19] activity is reduced); a test to determine CYP2C19 status (eg, genetic testing for CYP450 polymorphisms) is recommended. If impaired metabolism is confirmed, aspirin or the combination product aspirin/extended-release dipyridamole is a reasonable alternative.

Clopidogrel plus aspirin, if started during acute treatment, is given for only a short time (eg, < 3 months) because it has no advantage over aspirin alone in long-term secondary stroke prevention and results in more bleeding complications. Clopidogrel plus aspirin before and for ≥ 30 days after stenting is indicated, usually for ≤ 6 months; if patients cannot tolerate clopidogrel, ticlopidine 250 mg 2 times a day can be substituted.

Oral anticoagulants are indicated for secondary prevention of cardioembolic strokes (as well as primary prevention). Adjusted-dose warfarin (a vitamin K antagonist) with a target international normalized ratio (INR) of 2 to 3 is used for certain patients with nonvalvular or valvular atrial fibrillation. A target INR of 2.5 to 3.5 is used if patients have a mechanical prosthetic cardiac valve. Efficacious alternatives to warfarin for patients with nonvalvular atrial fibrillation include the following new anticoagulants:

Dabigatran (a direct thrombin inhibitor) 150 mg 2 times a day in patients without severe renal failure (creatinine clearance < 15 mL/minute) and/or liver failure (elevated INR)
Apixaban (a direct factor Xa inhibitor) 5 mg 2 times a day in patients ≥ 80 years, in patients with serum creatinine ≥ 1.5 mg/dL and creatinine clearance ≥ 25 mL/minute, or as an alternative to aspirin in patients who cannot take warfarin
Rivaroxaban (a direct factor Xa inhibitor) 20 mg once a day for patients without severe renal failure (creatinine clearance < 15 mL/minute)

The main advantage of these new anticoagulants is ease of use (eg, no need to check anticoagulation level with a blood test after the initial dose or to use a parenteral anticoagulant such as unfractionated heparin given by continuous infusion when transitioning from parenteral to oral anticoagulants). Their main disadvantage is lack of an antidote to reverse anticoagulation in case a hemorrhagic complication occurs; the exception is dabigatran, for which idarucizumab is an antidote ( 9). Efficacy and safety of combining any of these new anticoagulants with an antiplatelet drug have not been established.

Statins are used to prevent recurrent strokes; lipid levels must be decreased by substantial amounts. Atorvastatin 80 mg once a day is recommended for patients with evidence of atherosclerotic stroke and LDL (low-density lipoprotein) cholesterol ≥ 100 mg/dL. A reasonable LDL cholesterol target is a 50% reduction or a level of < 70 mg/dL. Other statins (eg, simvastatin, pravastatin) may be also used.

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