Ischemic Stroke

Dr Sura Al Zoubi

PhD,

MClinPharm

Lecture 9

Therapeutics

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References

• Pharmacotherapy: A Pathophysiologic Approach,

11e, Chapter 38: Stroke

• Guidelines for the Early Management of Patients

With Acute Ischemic Stroke: 2019 Update to the

2018 Guidelines for the Early Management of

Acute Ischemic Stroke: A Guideline for Healthcare

Professionals From the American Heart

Association/American Stroke Association

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INTRODUCTION

• Stroke is the leading cause of disability among adults and the fifth leading cause of death in the United States, behind cardiovascular disease, cancer, unintentional injuries, and chronic lower respiratory diseases.

• The incidence of stroke has been trending downward

• Although women have lower risk they have worse outcomes than men

• African Americans have stroke rates that are 1.5 times those of whites

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ETIOLOGY • Stroke is subdivided into either

1. Ischemic (87% of cases)

2. Hemorrhagic (13% of cases).

I. Subarachnoid hemorrhage (SAH)

II. Intracerebral hemorrhage (ICH).

• Hemorrhagic stroke, though less frequent in occurrence, has a significantly higher mortality than ischemic stroke, with a mortality rate of nearly 50% versus slight more than 25% for ischemic stroke

• Ischemic stroke is caused by;

1. Large artery atherosclerosis

2. Small artery disease

3. Cardioembolism 4

Risk Factors

Non modifiable

risk factors

Modifiable, well

documented

Potentially modifiable,

less well documented

• Age

• Race

• Sex

• Low birth

weight

• Genetic Factors

• Cigarette Smoking

• Hypertension

• Diabetes

• Asymptomatic carotid

stenosis

• Dyslipidemia

• Atrial fibrillation

• Sickle cell disease

• Poor diet

• Obesity

• Physical inactivity

• Other cardiac diseases

(coronary heart disease,

heart failure, PAD)

• Migraine

• Metabolic syndrome

• Drug and alcohol

abuse

• Inflammation and

infection

• Elevated lipoprotein

(a)

• Homocysteinemia

• Sleep-disordered

breathing

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PATHOPHYSIOLOGY

• Pathophysiology of ischemic stroke.

Diagram illustrating the three major

mechanisms underlying ischemic

stroke including

1. Occlusion of an intracranial vessel

by an embolus that arises from a

distant site (eg, cardiogenic

embolus),

2. In situ thrombosis of an intracranial

vessel, typically affecting the small

penetrating arteries, and

3. Hypoperfusion caused by flow-

limiting stenosis of a major

extracranial artery 6

• Occlusion of a cerebral artery reduction in cerebral blood flow ischemic stroke

• Cerebral autoregulation; Cerebral blood flow is maintained at an average rate of 50 mL/100 g per minute by blood vessels dilating and constricting in response to changes in blood pressure.

• This process can be impaired by atherosclerosis, chronic hypertension, and acute injury, such as stroke

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PATHOPHYSIOLOGY

• Insufficient oxygen supply in ischemic tissue leads to;

1. Adenosine triphosphate (ATP) depletion lactate accumulation and accumulation of intracellular sodium and water, leading to cytotoxic edema and eventual cell lysis.

2. Influx of calcium intracellularly lipases and proteases activation protein degradation and free fatty acid release from cellular membranes.

3. Release of excitatory amino acids, such as glutamate and aspartate, in ischemic tissue neuronal damage and production of damaging prostaglandins, leukotrienes, and reactive oxygen species.

• These processes occur within 2 to 3 hours from onset of ischemia and ultimately lead to cellular apoptosis and necrosis 8

PATHOPHYSIOLOGY

CLINICAL PRESENTATION

• Stroke describes patients with an episode of

neurologic dysfunction caused by focal

cerebral, spinal, or retinal infarction.

• Transient ischemic attack or TIA is a syndrome

of arterial ischemia with transient symptoms

(<24 hours)

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• 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, and vertigo and/or falling.

• Ischemic stroke is not usually painful, but some patients may complain of headache.

• Pain and headache, often severe, are more common with hemorrhagic stroke.

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• Signs

• The specific areas of neurologic deficit 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 deficits, and altered levels of consciousness

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• Laboratory Tests

• In acute stroke assessment of blood glucose,

platelet count, and coagulation parameters (eg,

prothrombin time, aPTT) are used to determine

treatment eligibility.

• Tests for hypercoagulable states (protein C/S

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. 12

Other Diagnostic Tests

• CT scan;

1. Hemorrhage; an area of hyperintensity (white)

2. Infarction; normal or hypointense (dark)

• It may take 24 hours before the CT scan will reveal

• MRI of the head will reveal areas of ischemia with higher resolution

• MRI with diffusion-weighted imaging (DWI) will reveal an evolving infarct within minutes of stroke onset

• CTA is recommended in patients with endovascular treatment indications.

• ECG can help determine whether the patient is presenting in atrial fibrillation

• TTE can identify cardiac valve abnormalities or wall-motion abnormalities as sources of emboli to the brain

• Carotid Doppler (CD) and transcranial Doppler (TCD) can be used to determine extracranial carotid artery stenosis and intracranial artery stenosis in patients unable to undergo CTA

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TREATMENT

Acute management

1. Airway, breathing and oxygenation

2. Blood pressure

3. Temperature

4. Glucose

5. IV alteplase

6. Mechanical thrombectomy

7. Antiplatelet

8. Anticoagulant

9. DVT prophylactic

Secondary prevention

1. Antiplatelet

2. Anticoagulant

3. Statin

4. Hypertension

5. Diabetes

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Desired Outcomes

• The goals of treatment of acute stroke are to;

1. Reduce the ongoing neurologic injury in the

acute setting to reduce mortality and long-

term disability,

2. Prevent complications secondary to

immobility and neurologic dysfunction, and

3. Prevent stroke recurrence.

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General Approach to Treatment

• Ensure the patient is stable from a respiratory and cardiac standpoint

• Determine whether the injury is ischemic or hemorrhagic by CT scan

• Patients with ischemic stroke should be evaluated for pharmacologic and mechanical reperfusion therapy.

• Patients with TIA require urgent assessment and intervention to reduce the risk of stroke

• Once the patient is out of the hyperacute phase (the first week) management efforts are focused on preventing worsening of stroke, minimizing complications, and instituting appropriate secondary prevention strategies 16

Emergency Evaluation and

Treatment

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Stroke Scales

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Head and Neck Imaging

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1. Airway, Breathing and Oxygenation

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2. Blood Pressure Management

• In general, it is more common for patients with ischemic stroke to present with elevated or normal blood pressure.

• However, hypotension and hypovolemia, if present, should be corrected to maintain systemic perfusion and end organ function.

• Data are limited to recommend pharmacologic agents to increase blood pressure in acute ischemic stroke above the typical normal parameters

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• For patients with elevated blood pressure who are otherwise eligible for alteplase, the treatment of hypertension to a goal systolic blood pressure less than 185 mm Hg and diastolic blood pressure of less than 110 mm Hg is recommended before thrombolytic administration.

• While data are limited, it is also reasonable to maintain blood pressure less than 185/110 mm Hg for patients undergoing mechanical thrombectomy

• For patients not requiring intravenous thrombolytic therapy or endovascular intervention, the use of “permissive hypertension” and allowing blood pressure to rise as high as 220/120 mm Hg for the first 48 to 72 hours is often used as early initiation of antihypertensive therapy does not prevent death or dependency.

• For patients with comorbid conditions requiring blood pressure management, a reduction of 15% is probably safe

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3. Body Temperature

• Identification of the source of fever and management is

recommended to maintain patients within normothermia ranges.

• Pharmacologic and nonpharmacologic interventions can be

considered and applied. Data are limited to support induced

hypothermia and this intervention should be done only in a

controlled, clinical trial setting

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4. Blood Glucose • Blood glucose <60 mg/dL [3.3 mmol/L] or >180 mg/dL [10.0 mmol/L] should be

treated)

• IV alteplase is recommended in otherwise eligible patients with initial glucose

levels >50 mg/dL subsequently normalized and who are otherwise eligible may be

reasonable

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• Alteplase use is associated with a high risk for bleeding, including intracranial hemorrhage, and adherence to guideline-recommended protocol is essential to achieving a positive outcome and minimizing the risk.

• The essentials of this protocol can be summarized as

1. stroke team activation,

2. CT scan to rule out hemorrhage,

3. treatment as early as possible within 4.5 hours of symptom onset,

4. meeting inclusion and exclusion criteria,

5. administration of alteplase 0.9 mg/kg total dose given as 10% as a bolus over 1 minute, remaining 90% over 1 hour, and maximum dose of 90 mg,

6. avoidance of antithrombotic therapy (anticoagulant or antiplatelet) for 24 hours after alteplase,

7. close patient monitoring for elevated blood pressure, neurologic status, and hemorrhage.

• Endovascular intervention is not a contraindication to alteplase and patients eligible for alteplase should receive pharmacologic treatment in addition to mechanical thrombectomy

5. IV Alteplase Pharmacologic Therapy

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6. Mechanical thrombectomy Nonpharmacologic Therapy

• Patients with ICA or the M1 segment of the MCA;

1. Within 6 hours Thrombectomy

2. 6 to 24 hours Thrombectomy in selected patients

• Patients with ICA and M1 MCA arterial occlusions;

1. Within 24 hours Endovascular intervention if imaging studies suggest a significant area of salvageable penumbra is present

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• In patients with cerebellar infarction and

significant swelling surgical

decompression can be lifesaving.

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• Decompressive hemicraniectomy is a surgical procedure that can be

done to reduce intracranial pressure, typically due to cerebral edema, and

can reduce mortality and improve functional outcome;

1. <60 years with unilateral MCA infarcts and significant cerebral edema,

it reduces mortality by almost 50% and improve favorable neurologic

outcomes at one year

2. > 60 years likelihood of favorable neurologic outcome is less robust.

• In secondary prevention, carotid endarterectomy of an ulcerated and/or stenotic

carotid artery is a very effective (recurrent stroke risk can be reduced by up to 48%

compared with medical therapy alone when combined with aspirin 325 mg daily).

• In patients younger than 70 years, carotid stenting is a less invasive alternative and

can be effective in reducing recurrent stroke risk when combined with aspirin and

clopidogrel therapy.

• There are conflicting studies regarding efficacy and adverse effects when comparing

the two procedures.

• However, in patients with intracranial stenosis, aggressive medical management was

shown to be superior to stenting in reducing recurrent stroke

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7. Antiplatelet • Early aspirin therapy within 24 to 48 hours from symptom onset should be given to stroke

patients unless allergy or other contraindication prevents the use.

• For patients receiving alteplase, aspirin and other antithrombotics are generally held for 24 hours after alteplase administration to reduce risk of hemorrhage

• Data are limited to describe acute use of nonaspirin antiplatelet agents in the acute stroke phase apart from combination therapy investigations, but it may be reasonable to use an alternate antiplatelet agent in acute stroke patients who have an allergy or severe contraindication to aspirin.

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8. Anticoagulants

• Use of urgent anticoagulation (eg, unfractionated heparin or low-molecular-weight heparin) is not routinely recommended in the early phase of acute ischemic stroke treatment.

• There are data investigating the clinical benefit of urgent anticoagulation in the setting of nonocclusive intraluminal thrombus in acute stroke, but the data are limited.

• Restricted use on a case-by-case basis or in a clinical trial setting may be considered.

• Use and benefit of immediate anticoagulation for nonstroke indications (eg, prophylaxis for venous thromboembolism) should be weighed against the risk of intracranial hemorrhagic conversion in acute ischemic stroke patients.

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9. DVT prophylaxis

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Secondary Prevention

Secondary Prevention

• Antiplatelet therapy is the cornerstone of antithrombotic therapy for the secondary prevention of ischemic stroke and should be used in noncardioembolic strokes.

1. Aspirin,

2. Extended-release dipyridamole plus aspirin, and

3. Clopidogrel

• In patients with atrial fibrillation and a presumed cardiac source of embolism, oral anticoagulation with either vitamin K antagonists (warfarin), apixaban, dabigatran, or rivaroxaban is recommended for secondary stroke prevention. (See AF lecture)

• Other pharmacotherapy recommended for secondary prevention of stroke includes blood pressure lowering and statin therapy.

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1. Antiplatelet

• All patients who have had an acute ischemic stroke or TIA should receive long-term antithrombotic therapy for secondary prevention.

• In patients with noncardioembolic stroke, this will be some form of antiplatelet therapy.

• In a study, clopidogrel was slightly more effective than aspirin and had a similar incidence of adverse effects.

• The tolerability of clopidogrel 75 mg/day is at least as good as medium-dose (325 mg/day) aspirin, and there is less GI bleeding

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• The use of early aspirin to reduce long-term death and disability owing to

ischemic stroke is supported by two large, randomized clinical trials.

• In the International Stroke Trial (IST),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.

• There was a small but significant increase in hemorrhagic transformation

of the infarction.

• Overall, the beneficial effects of early aspirin have been embraced and

adopted into clinical guidelines.

• Dose (50 to 975 mg/day) use the lowest effective aspirin dosage

thereby limiting the risk of gastrointestinal (GI) adverse effects

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Aspirin

Clopidogrel

• 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) aspirin, and GI bleeding is less.

• Clopidogrel is associated with an increased risk of diarrhea and rash, but discontinuation rates owing to adverse effects are similar to those with aspirin 325 mg/day (5.3% to 6%, respectively).

• Clopidogrel is as effective and safe as aspirin. Clopidogrel is an alternative to aspirin in secondary prevention of stroke.

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Extended-Release Dipyridamole Plus

Aspirin • Early studies of the role of dipyridamole in stroke prevention failed to show a

benefit over that realized by aspirin 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.

• The combination of sustained-release dipyridamole and aspirin is an acceptable alternative for secondary prevention of stroke when initial secondary prevention has failed.

• 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 aspirin, in order to reduce costs, is unproven and should be discouraged.

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2. Oral Anticoagulants

• Oral anticoagulation is the treatment of choice

for the prevention of stroke in patients with

atrial fibrillation

• For more information see AF lecture

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3. Blood Pressure Management • Elevated BP is very common in ischemic stroke patients, and treatment of hypertension in

these patients is associated with a decreased risk of stroke recurrence.

• Adults with previously treated hypertension who experience a stroke or transient ischemic attack (TIA) should be restarted on antihypertensive treatment after the first few days of the index event to reduce the risk of recurrent stroke and other vascular events.

• For adults who experience a stroke or TIA, treatment with a thiazide diuretic, angiotensin-converting enzyme (ACE) inhibitor, or angiotensin receptor blocker, or combination treatment consisting of a thiazide diuretic plus ACE inhibitor, is useful.

• Selection of specific drugs should be individualized on the basis of patient comorbidities and agent pharmacological class.

• Adults not previously treated for hypertension who experience a stroke or TIA and have an established BP of 140/90 mm Hg or higher should be prescribed antihypertensive treatment a few days after the index event to reduce the risk of recurrent stroke and other vascular events.

• For adults who experience a stroke or TIA, a BP goal of less than 130/80 mm Hg may be reasonable.

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4. Statins • Statin therapy is recommended for all ischemic stroke patients, regardless

of baseline cholesterol, to reduce stroke recurrence.

• It is now recommended that patients age 75 or younger experiencing ischemic stroke of presumed atherosclerotic origin be treated with high-intensity statin therapy for secondary stroke prevention with a target of achieving a 50% or greater reduction in low-density lipoprotein (LDL) cholesterol.

• For patients older than 75, moderate- or high-intensity statin therapy can be initiated as tolerated.

• If the patient is on maximally tolerated statin therapy, but still has an LDL cholesterol ≥70 mg/dL (1.81 mmol/L), ezetimibe may be initiated.

• In very high-risk who are taking maximally tolerated statins and ezetimibe with LDL cholesterol ≥70 mg/dL (1.81 mmol/L), a proprotein convertase sutilisin/kexin type 9 (PCSK9) inhibitor may be considered

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5. Diabetes

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EVALUATION OF THERAPEUTIC

OUTCOMES

• Patients with acute stroke should be monitored intensely for the development of neurologic worsening (recurrence or extension of stroke), complications (venous thromboembolism or infection), and adverse effects from pharmacologic or nonpharmacologic interventions.

• The most common reasons for deterioration in a stroke patient are

1. Extension of the original lesion—ischemic or hemorrhagic—in the brain,

2. Development of cerebral edema and raised intracranial pressure,

3. Hypertensive emergency,

4. Infection (urinary and respiratory most common),

5. Venous thromboembolism (DVT and PE),

6. Electrolyte abnormalities and cardiac rhythm disturbances (can be associated with brain injury),

7. Recurrent stroke. 50

Monitoring Stroke Therapy in Hospitalized

Patients

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2 hours

16 hours

Thank You

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