Birzeit University

Access Provided by:

DiPiro: Pharmacotherapy A Pathophysiologic Approach, 12e

Chapter 39: Stroke

Melody Ryan; Melissa Nestor

KEY CONCEPTS

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.

In patients with an ischemic stroke and a blood pressure (BP) <220/120 mm Hg without comorbid conditions requiring acute hypertensive
treatment, the acute lowering of BP in the first 48 to 72 hours after stroke onset does not improve survival or the level of dependency;
“permissive hypertension” (BP up to 220/120 mm Hg) is often allowed. In patients with intracranial hemorrhage and elevated systolic blood
pressure (SBP) between 150 and 220 mm Hg, the acute lowering of SBP to lower than 140 mm Hg is safe and may improve functional outcomes.

Thrombectomy is strongly recommended for patients with anterior circulation arterial occlusion in the internal carotid artery (ICA) or the
M1 segment of the middle cerebral artery (MCA) who are within 6 hours of symptom onset and may be considered in select patients within 6 to
24 hours of symptom onset.

In patients with ischemic stroke and 70% to 99% stenosis of the carotid artery, carotid endarterectomy or carotid stenting should be
performed.

Early pharmacologic reperfusion (initiated less than 4.5 hours from symptom onset) with intravenous alteplase has been shown to improve
functional ability after 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 high­risk patients.

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.

Statin therapy is recommended for all ischemic stroke patients, regardless of baseline cholesterol, to reduce stroke recurrence.

BEYOND THE BOOK

BEYOND THE BOOK

Watch the video entitled “What is a stroke?” (https://youtu.be/QIAI6KOwKII">https://youtu.be/QIAI6KOwKII) in Khan Academy. This 11­minute video
provides an overview of stroke and is useful to enhance understanding of stroke pathophysiology.

Downloaded 2022­10­24 2:51 P Your IP is 41.233.255.202

Chapter 39: Stroke, Melody Ryan; Melissa Nestor Page 1 / 35
INTRODUCTION
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility

Stroke is the leading cause of disability among adults and the fifth leading cause of death in the United States, behind cardiovascular disease, cancer,
 Statin therapy is recommended for all ischemic stroke patients, regardless of baseline cholesterol, to reduce stroke recurrence.
Birzeit University
Access Provided by:

BEYOND THE BOOK

BEYOND THE BOOK

Watch the video entitled “What is a stroke?” (https://youtu.be/QIAI6KOwKII">https://youtu.be/QIAI6KOwKII) in Khan Academy. This 11­minute video
provides an overview of stroke and is useful to enhance understanding of stroke pathophysiology.

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.1 Although the incidence of stroke has been trending downward, approximately 795,000
strokes occur annually, contributing to nearly 148,000 deaths each year.2 Aggressive efforts to organize stroke care at the local and regional levels and
increased utilization of evidence­based recommendations and national guidelines may have contributed to the improved outcomes.

EPIDEMIOLOGY
There are about 7.6 million stroke survivors in the United States and stroke is the leading cause of adult disability, with women having worse outcomes
than men.2 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 nearly $50 billion.2

Not all groups have benefitted equally from advances in care and prevention of stroke. Black Americans have stroke rates that are 1.5 times higher than
White Americans; rates are up to four times higher at younger ages.2 Genome­wide studies provide some evidence that part of this racial disparity is
genetic. However, age­adjusted death rates for stroke are still 1.6 times higher for Black men compared to White men and 1.3 times higher for Black
women compared to White women.2 In addition, geographic disparity in stroke incidence exists, such that many states in the southeastern United
States have stroke mortality rates 30% to 40% higher than the national average.2 Lastly, case fatality due to hemorrhagic stroke has not declined in the
past decade, with 30­day rates remaining around 46%.2

ETIOLOGY

Stroke is subdivided into either ischemic or hemorrhagic types (87% and 13%, respectively).2 Hemorrhagic stroke includes subarachnoid
hemorrhage (SAH) and intracerebral hemorrhage (ICH). SAH occurs when blood enters the subarachnoid space, which can occur due to trauma,
rupture of an intracerebral aneurysm, or rupture of an arteriovenous malformation (AVM). ICH, however, occurs when bleeding occurs in the brain
parenchyma itself, with the formation of a hematoma within the brain. Uncontrolled hypertension is the most common cause for ICH, but
antithrombotic therapy, cerebral amyloid angiopathy, and some drugs of abuse are also associated with ICH.3 Hemorrhagic stroke, though less
frequent in occurrence, has significantly higher mortality than ischemic stroke and is dependent on the quality and availability of critical care. In high­
income countries, the mortality rate is 25% to 30%, but it is 30% to 48% in low­ and middle­income countries.3

Ischemic stroke is caused by occlusion within a cerebral artery or emboli from a more proximal source resulting in occlusion of a cerebral artery.
Atherosclerosis of large arteries, either intracranial or extracranial, as well as small artery damage, can give rise to ischemic stroke. Emboli can also
arise centrally from the heart in patients with atrial fibrillation, valvular heart disease, or other prothrombogenic heart problems and are responsible
for approximately 25% of ischemic stroke. While large artery atherosclerosis, small artery disease, and cardioembolism comprise the majority of
ischemic stroke mechanisms, the cause of stroke is undetermined in some cases.2 Determining the stroke mechanism (eg, cardiogenic mechanism vs
other causes) is important when selecting the most appropriate long­term pharmacotherapy in stroke patients.

Risk Factors

Risk factors for ischemic stroke can be described as nonmodifiable or modifiable, with some risk factors more well­documented than others. The main
risk factors of ischemic stroke are listed in TABLE 39­1.4 The risk of stroke doubles for each decade older than 55 years. Men are at a higher risk of
ischemic stroke than women at a younger age, but women have higher mortality and lifetime risk of ischemic stroke overall. Individuals who identify as
Black, Asian­Pacific
Downloaded Islanders,
2022­10­24 2:51orPHispanic
Your IPhave higher rates of death from ischemic stroke compared to those who identify as White.4
is 41.233.255.202
Chapter 39: Stroke,for
Recommendations Melody Ryan;
ischemic Melissa
stroke Nestorfocus on aggressive management of modifiable, well­documented risk factors.
prevention Page 2 / 35
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
TABLE 39­1
Risk Factors for Ischemic Stroke
Risk Factors
Birzeit University
Risk factors for ischemic stroke can be described as nonmodifiable or modifiable, with some risk factors more well­documented than others. The main
Access Provided by:

risk factors of ischemic stroke are listed in TABLE 39­1.4 The risk of stroke doubles for each decade older than 55 years. Men are at a higher risk of
ischemic stroke than women at a younger age, but women have higher mortality and lifetime risk of ischemic stroke overall. Individuals who identify as
Black, Asian­Pacific Islanders, or Hispanic have higher rates of death from ischemic stroke compared to those who identify as White.4
Recommendations for ischemic stroke prevention focus on aggressive management of modifiable, well­documented risk factors.

TABLE 39­1
Risk Factors for Ischemic Stroke

Nonmodifiable Risk Factors

Age
Race
Sex
Low birth weight
Genetic Factors

Modifiable, Well Documented

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, peripheral arterial disease)

Potentially Modifiable, Less Well Documented

Migraine
Metabolic syndrome
Drug and alcohol abuse
Inflammation and infection
Elevated lipoprotein (a)
Homocysteinemia
Patent foramen ovale
Sleep­disordered breathing

Data from Reference 4.

The most common modifiable, well­documented risk factors for ischemic stroke include hypertension, cigarette smoking, diabetes, atrial fibrillation,
and dyslipidemia. Hypertension is the most common risk factor, affecting up to one in three adults in the United States. Cardiac disease, including
coronary artery disease, heart failure, left ventricular hypertrophy, and particularly atrial fibrillation, is also a very important risk factor. Atrial
fibrillation increases an individual’s risk of ischemic stroke to 5% to 20% per year, depending on concomitant comorbidities. Diabetes mellitus,
dyslipidemia, and cigarette smoking contribute to atherogenic disease and increase the risk of ischemic stroke.4

PATHOPHYSIOLOGY
Ischemic Stroke
Downloaded 2022­10­24 2:51 P Your IP is 41.233.255.202
Ischemic39:
Chapter stroke is theMelody
Stroke, manifestation of neurologic
Ryan; Melissa Nestordeficit due to occlusion of a cerebral artery, causing a reduction in cerebral blood flow and neuronal
Page 3 / 35
©2022 McGraw
ischemia. Hill. All Rights Reserved.
The pathophysiologic mechanismsTerms of Usestroke
of ischemic • Privacy Policy • Notice
are depicted • Accessibility
in Fig. 39­1. These arterial occlusions are most commonly due to artery­
to­artery emboli, cardiac sources of emboli, or by vascular changes leading to occlusion of the cerebral artery itself. Cerebral blood flow is maintained
at an average rate of 50 mL/100 g per minute over a wide range of blood pressure (mean arterial pressures of 50­150 mm Hg) by a process called
dyslipidemia, and cigarette smoking contribute to atherogenic disease and increase the risk of ischemic stroke.4
Birzeit University
Access Provided by:
PATHOPHYSIOLOGY
Ischemic Stroke

Ischemic stroke is the manifestation of neurologic deficit due to occlusion of a cerebral artery, causing a reduction in cerebral blood flow and neuronal
ischemia. The pathophysiologic mechanisms of ischemic stroke are depicted in Fig. 39­1. These arterial occlusions are most commonly due to artery­
to­artery emboli, cardiac sources of emboli, or by vascular changes leading to occlusion of the cerebral artery itself. Cerebral blood flow is maintained
at an average rate of 50 mL/100 g per minute over a wide range of blood pressure (mean arterial pressures of 50­150 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. Decreased cerebral blood flow due to arterial occlusion can lead to infarction
of cerebral tissue. Surrounding a core area of infarct is tissue that is ischemic but may maintain membrane integrity and is referred to as the ischemic
penumbra.5 This penumbra is the area of brain tissue that is potentially salvageable with urgent pharmacologic and endovascular interventions in
acute ischemic stroke.

FIGURE 39­1

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 (eg, cardiogenic embolus), in situ thrombosis of an intracranial vessel, typically
affecting the small penetrating arteries, and hypoperfusion caused by flow­limiting stenosis of a major extracranial artery. (Reproduced, with
permission, from Smith WS, Johnston S, Hemphill J III. Ischemic stroke. In: Jameson J, Fauci AS, Kasper DL, et al., eds. Harrison’s Principles of Internal
Medicine. 20th ed. New York, NY: McGraw Hill; 2018.)

Insufficient oxygen supply in ischemic tissue leads to adenosine triphosphate (ATP) depletion and anaerobic metabolism. This results in an
accumulation of intracellular lactate, sodium, and water, which may cause cytotoxic edema and eventual cell lysis. There is also an influx of
intracellular calcium leading to activation of lipases and proteases that degrade proteins and release free fatty acids from cellular membranes.
Additionally, excitatory amino acids, such as glutamate and aspartate, are released in ischemic tissue that perpetuate neuronal damage and
Downloaded
production of2022­10­24 2:51 P Your IPleukotrienes,
damaging prostaglandins, is 41.233.255.202
and reactive oxygen species. These processes occur within 2 to 3 hours from the onset of
Chapter 39: Stroke, Melody Ryan; Melissa Nestor Page 4 / 35
ischemia and, ultimately, lead toReserved.
cellular apoptosis and necrosis.5
©2022 McGraw Hill. All Rights Terms of Use • Privacy Policy • Notice • Accessibility

Hemorrhagic Stroke
 Birzeit University
Insufficient oxygen supply in ischemic tissue leads to adenosine triphosphate (ATP) depletion and anaerobic metabolism. This resultsAccess
in anProvided by:
accumulation of intracellular lactate, sodium, and water, which may cause cytotoxic edema and eventual cell lysis. There is also an influx of
intracellular calcium leading to activation of lipases and proteases that degrade proteins and release free fatty acids from cellular membranes.
Additionally, excitatory amino acids, such as glutamate and aspartate, are released in ischemic tissue that perpetuate neuronal damage and
production of damaging prostaglandins, leukotrienes, and reactive oxygen species. These processes occur within 2 to 3 hours from the onset of
ischemia and, ultimately, lead to cellular apoptosis and necrosis.5

Hemorrhagic Stroke

Hemorrhagic stroke causes neuronal damage by a variety of mechanisms and timelines. In patients with ICH, the hematoma causes primary injury and
mechanical compression of the brain parenchyma itself. Early hematoma expansion, which may occur in up to 38% of patients within 3 hours of ICH
onset, is associated with worsened functional outcome and increased mortality. The highest rates of mortality are associated with a low Glasgow Coma
Score (GCS) on presentation (GCS 3­4), ICH volume greater than 30 cc (mL), intraventricular extension, brain stem location, and age greater than 80.6
Secondary mechanisms of injury in ICH patients are mediated by subsequent inflammatory response, cerebral edema, and damage from blood
product degradation.3

CLINICAL PRESENTATION
The term stroke describes patients with an episode of neurologic dysfunction caused by focal cerebral, spinal, or retinal infarction. The syndrome of
arterial ischemia with transient symptoms (<24 hours) and without evidence of infarction is a transient ischemic attack (TIA). Appropriate patient
history obtainment helps determine the nature of symptom onset and duration of neurologic dysfunction. The location of the central nervous system
(CNS) injury and its reference to a specific arterial distribution in the brain are determined through neurologic examination and confirmed by imaging
studies such as computed tomography (CT) and magnetic resonance imaging (MRI). The main arterial supply to the cerebral hemispheres is illustrated
in Fig. 39­2 and Fig. 39­3. Vascular imaging with computed tomography angiography (CTA) can aid clinicians in determining the cause of stroke and
whether urgent mechanical intervention is necessary.

FIGURE 39­2

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 Smith WS, Johnston S, Hemphill J III. Cerebrovascular Diseases. In: Jameson J, Fauci AS, Kasper DL, et al., eds.
Harrison’s Principles of Internal Medicine. 20th ed. New York, NY: McGraw Hill; 2018.)

Downloaded 2022­10­24 2:51 P Your IP is 41.233.255.202

Chapter 39: Stroke, Melody Ryan; Melissa Nestor Page 5 / 35
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
FIGURE 39­2

Birzeit University
Diagram of a cerebral hemisphere in coronal section showing the territories of the major cerebral vessels branching from the internal carotid arteries.
Access Provided by:
(Reproduced, with permission, from Smith WS, Johnston S, Hemphill J III. Cerebrovascular Diseases. In: Jameson J, Fauci AS, Kasper DL, et al., eds.
Harrison’s Principles of Internal Medicine. 20th ed. New York, NY: McGraw Hill; 2018.)

FIGURE 39­3

Diagram of the posterior circulation, showing the intracranial vertebral arteries forming the basilar artery that gives off the anterior inferior cerebellar,
superior cerebellar, and posterior cerebral arteries. The posterior inferior cerebellar artery arises from each of the vertebral segments. The majority of
brainstem blood flow arises from numerous deep branches of the basilar artery that penetrate directly into the brainstem. (Reproduced, with
permission, from Smith WS, Johnston S, Hemphill J III. Cerebrovascular Diseases. In: Jameson J, Fauci AS, Kasper DL, et al., eds. Harrison’s Principles
of Internal Medicine. 20th ed. New York, NY: McGraw Hill; 2018.)

Downloaded 2022­10­24 2:51 P Your IP is 41.233.255.202

Chapter 39: Stroke, Melody Ryan; Melissa Nestor Page 6 / 35
CLINICAL PRESENTATION: Stroke
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
General
superior cerebellar, and posterior cerebral arteries. The posterior inferior cerebellar artery arises from each of the vertebral segments. The majority of
Birzeit University
brainstem blood flow arises from numerous deep branches of the basilar artery that penetrate directly into the brainstem. (Reproduced, with
Access Provided by:
permission, from Smith WS, Johnston S, Hemphill J III. Cerebrovascular Diseases. In: Jameson J, Fauci AS, Kasper DL, et al., eds. Harrison’s Principles
of Internal Medicine. 20th ed. New York, NY: McGraw Hill; 2018.)

CLINICAL PRESENTATION: Stroke

General

The patient may not be able to reliably report the history due to cognitive or language deficits. A reliable history may have to come from a family
member or witness.

Symptoms

The patient may complain of weakness on one side of the body, inability to speak, loss of vision, 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.

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.

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 well­known risk factors.

Other Diagnostic Tests

CT scan of the head will reveal an area of hyperdensity (white) in patients with hemorrhage and will be normal or hypodense (dark) in patients
with infarction. It may take 24 hours before the CT scan will reveal the area of infarction.

MRI of the head will reveal areas of ischemia with higher resolution and an MRI with diffusion­weighted imaging (DWI) will reveal an evolving
Downloaded 2022­10­24 2:51 P Your IP is 41.233.255.202
infarct
Chapter within minutes
39: Stroke, Melody of stroke
Ryan; onset.Nestor
Melissa Page 7 / 35
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
Vascular imaging with CTA is recommended in patients with endovascular treatment indications. CTA can identify both acute treatment
candidacy as well as identify intracranial and extracranial arterial stenosis.
 Birzeit University
Access Provided by:

CLINICAL PRESENTATION: Stroke

General

The patient may not be able to reliably report the history due to cognitive or language deficits. A reliable history may have to come from a family
member or witness.

Symptoms

The patient may complain of weakness on one side of the body, inability to speak, loss of vision, 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.

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.

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 well­known risk factors.

Other Diagnostic Tests

CT scan of the head will reveal an area of hyperdensity (white) in patients with hemorrhage and will be normal or hypodense (dark) in patients
with infarction. It may take 24 hours before the CT scan will reveal the area of infarction.

MRI of the head will reveal areas of ischemia with higher resolution and an MRI with diffusion­weighted imaging (DWI) will reveal an evolving
infarct within minutes of stroke onset.

Vascular imaging with CTA is recommended in patients with endovascular treatment indications. CTA can identify both acute treatment
candidacy as well as identify intracranial and extracranial arterial stenosis.

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

TTE can identify cardiac valve abnormalities or wall­motion abnormalities as sources of emboli to the brain. A “bubble study” in which a
solution with tiny bubbles is injected intravenously can be done to look for an intra­arterial shunt indicating an atrial­septal defect or a patent
foramen ovale. The bubbles can be seen moving through the heart chambers during the TTE.

In patients unable to undergo CTA, carotid Doppler (CD) and transcranial Doppler (TCD) can be used to determine extracranial carotid artery
stenosis and intracranial artery stenosis.

PATIENT CARE PROCESS

Downloaded
Patient Care2022­10­24
Process for 2:51
AcuteP Ischemic
Your IP is 41.233.255.202
Stroke
Chapter 39: Stroke, Melody Ryan; Melissa Nestor Page 8 / 35
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
 stenosis and intracranial artery stenosis.
Birzeit University
Access Provided by:

PATIENT CARE PROCESS

Patient Care Process for Acute Ischemic Stroke

Collect

Patient characteristics (eg, age, sex, race)

Patient medical history (personal and family)

Social history (eg, tobacco/ethanol use)

Current medications including nonprescription aspirin/nonsteroidal anti­inflammatory drug (NSAID) use, herbal products, dietary
supplements, and prior antiplatelet and anticoagulant medication use

Medication allergies

Symptoms (time of onset, duration)

Objective data

Blood pressure (BP), heart rate, respiratory rate, height, weight

Labs including hemoglobin, platelets, serum creatinine, activated partial thromboplastin time (aPTT), prothrombin time, blood glucose,
troponin

Noncontrast computed tomography (CT) scan, magnetic resonance imaging (MRI), and/or computed tomography angiography (CTA) may
be needed

Neurologic examination (eg, National Institutes of Health Stroke Scale [NIHSS] score)

Electrocardiogram (ECG) and, in some patients, transthoracic echocardiogram (TTE)

Assess

Hemodynamic stability (eg, systolic blood pressure [SBP] <110 mm Hg, diastolic blood pressure [DBP] <185 mm Hg, if candidate for tissue
plasminogen activator candidate; otherwise, BP less than 220/120 mm Hg; O2­sat >94% [0.94]; temperature <38°C [100.4°F])
Downloaded 2022­10­24 2:51 P Your IP is 41.233.255.202
Chapter 39: Stroke, Melody Ryan; Melissa Nestor Page 9 / 35
©2022Blood
McGrawglucose
Hill. (<60 mg/dLReserved.
All Rights [3.7 mmol/L] or >180
Terms mg/dL
of Use [10.0 mmol/L]
• Privacy Policy •should
Noticebe treated)
• Accessibility

Presence of active bleeding and/or bleeding risk factors (Table 39­6)

 Electrocardiogram (ECG) and, in some patients, transthoracic echocardiogram (TTE) Birzeit University
Access Provided by:
Assess

Hemodynamic stability (eg, systolic blood pressure [SBP] <110 mm Hg, diastolic blood pressure [DBP] <185 mm Hg, if candidate for tissue
plasminogen activator candidate; otherwise, BP less than 220/120 mm Hg; O2­sat >94% [0.94]; temperature <38°C [100.4°F])

Blood glucose (<60 mg/dL [3.7 mmol/L] or >180 mg/dL [10.0 mmol/L] should be treated)

Presence of active bleeding and/or bleeding risk factors (Table 39­6)

Patient’s candidacy for tissue plasminogen activator treatment (Table 39­2)or thrombectomy

Presence of dysphagia (swallowing disorder)

Plan

Aspirin within 24 to 48 hours unless contraindicated; delay for 24 hours if the patient has been given tissue plasminogen activator

Antiplatelet drug therapy regimen including specific medication(s), dose, frequency, and duration OR oral anticoagulant, if the patient has
atrial fibrillation (see Table 39­2)

Evaluation for carotid endarterectomy or carotid stenting

Prophylaxis for venous thromboembolism, if immobile

Nutritional plan; if the patient has dysphagia, nutrition via nasogastric tube or percutaneous gastrostomy tube

Treat and manage stroke risk factors (Table 39­2) (eg, BP control, dyslipidemia, diabetes)

Monitoring parameters including efficacy (eg, stroke symptoms) and safety (eg, signs and symptoms of bleeding [all antiplatelets and oral
anticoagulants], headache [dipyridamole]); frequency and timing of follow­up

Patient education (eg, the purpose of treatment, dietary and lifestyle modification, invasive procedures, drug­specific information, medication
administration)

Self­monitoring for stroke recurrence, the occurrence of bleeding, and when to seek emergency medical attention

Referrals to other providers when appropriate (eg, physical therapist, occupational therapist, behavioral health, dietician)

Implement⁎

Provide patient education regarding all elements of the treatment plan

Use motivational interviewing and coaching strategies to maximize adherence

Schedule follow­up

Follow­up: Monitor and Evaluate

Improvement of stroke symptoms; neurological examination

Presence of adverse drug reactions (eg, bleeding [all medications], gastrointestinal upset [aspirin], headache [dipyridamole], cerebral edema,
seizures)

Patient adherence to treatment plan using multiple sources of information

Adherence to recommended follow­up appointments (eg, neurology, physical therapy)

Assess for poststroke depression

*
Collaborate with patient, caregivers, and other healthcare professionals.

Downloaded 2022­10­24 2:51 P Your IP is 41.233.255.202

Chapter 39: Stroke, Melody Ryan; Melissa Nestor
TREATMENT Page 10 / 35
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility

Desired Outcomes
 Adherence to recommended follow­up appointments (eg, neurology, physical therapy)
Birzeit University
Assess for poststroke depression Access Provided by:

*
Collaborate with patient, caregivers, and other healthcare professionals.

TREATMENT
Desired Outcomes

The goals of treatment of acute stroke are to (a) minimize the ongoing neurologic injury in the acute setting to reduce mortality and long­term
disability, (b) prevent complications secondary to immobility and neurologic dysfunction, and (c) prevent stroke recurrence. Primary prevention of
stroke is described in the Chapter 30 (Hypertension), Chapter e31 (Acute Hypertensive Crisis), and Chapter 32 (Dyslipidemia).4

General Approach to Treatment

Patients with presumed acute stroke should have a CT scan performed urgently to identify the type of injury (eg, ischemic or hemorrhagic),
provided respiratory and cardiac indices are stable. Ischemic stroke patients presenting within hours of symptom onset should be evaluated for
pharmacologic and mechanical reperfusion therapy. Patients with TIA require urgent assessment and intervention to reduce the risk of stroke, which
is highest in the first few days after TIA.4

In the absence of comorbid conditions, in patients with an acute ischemic stroke and uncontrolled hypertension with a BP <220/120 mm Hg, acutely
lowering BP in the first 48 to 72 hours does not prevent death or improve the level of dependency. Therefore, “permissive hypertension” is often part
of routine care in these patients. However, for patients who are candidates for alteplase or those with comorbid conditions, such as aortic dissection,
acute myocardial infarction, pulmonary edema, or hypertensive encephalopathy, treatment of acute hypertension may be required. If BP is treated, the
use of short­acting and easily titrated agents, such as labetalol or nicardipine/clevidipine, is preferred. See Chapter e31 ­ Acute Hypertensive Crisis.
Table 39­2 outlines current recommendations regarding the management of arterial hypertension in patients with acute ischemic stroke. In patients
with ICH and elevated BP, the acute lowering of SBP to 140 mm Hg has been shown to be safe and may improve functional outcome.6

TABLE 39­2
Blood Pressure Treatment Guidelines in Stroke

Recommendation Class (Strength) of Level

Recommendationa (Quality)
of

Evidenceb

Ischemic Stroke with Alteplase Treatment

Pre­alteplase: lower BP to SBP <185 mm Hg and DBP <110 mm Hg I B­NR

Post­alteplase: maintain SBP <180 mm Hg and DBP <105 mm Hg for 24 hours

Ischemic Stroke without Alteplase Treatment

Treatment benefit uncertain/not recommended unless BP >220/120 mm Hg IIb C­EO

If comorbid conditions (eg, acute coronary event, acute heart failure, aortic dissection, symptomatic I C­EO
intracranial hemorrhage, preeclampsia/eclampsia) are present that require acute lowering of BP, lowering BP
by 15% is probably safe)

Ischemic Stroke with Mechanical Thrombectomy without Fibrinolytic Treatment

It is reasonable to maintain BP ≤ 185/110 mm Hg before the procedure IIb C­EO

Downloaded 2022­10­24
Intracranial 2:51 P Your IP is 41.233.255.202
Hemorrhage
Chapter 39: Stroke, Melody Ryan; Melissa Nestor Page 11 / 35
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
Treatment is reasonable for ICH patients with SBP >220 mm Hg IIb C
For ICH patients with SBP 150­220 mm Hg, acute lowering of SBP to 140 mm Hg is safe I A
Table 39­2 outlines current recommendations regarding the management of arterial hypertension in patients with acute ischemic stroke. In patients
with ICH and elevated BP, the acute lowering of SBP to 140 mm Hg has been shown to be safe and may improve functional outcome.6 Birzeit University
Access Provided by:
TABLE 39­2
Blood Pressure Treatment Guidelines in Stroke

Recommendation Class (Strength) of Level

Recommendationa (Quality)
of

Evidenceb

Ischemic Stroke with Alteplase Treatment

Pre­alteplase: lower BP to SBP <185 mm Hg and DBP <110 mm Hg I B­NR

Post­alteplase: maintain SBP <180 mm Hg and DBP <105 mm Hg for 24 hours

Ischemic Stroke without Alteplase Treatment

Treatment benefit uncertain/not recommended unless BP >220/120 mm Hg IIb C­EO

If comorbid conditions (eg, acute coronary event, acute heart failure, aortic dissection, symptomatic I C­EO
intracranial hemorrhage, preeclampsia/eclampsia) are present that require acute lowering of BP, lowering BP
by 15% is probably safe)

Ischemic Stroke with Mechanical Thrombectomy without Fibrinolytic Treatment

It is reasonable to maintain BP ≤ 185/110 mm Hg before the procedure IIb C­EO

Intracranial Hemorrhage

Treatment is reasonable for ICH patients with SBP >220 mm Hg IIb C

For ICH patients with SBP 150­220 mm Hg, acute lowering of SBP to 140 mm Hg is safe I A

Pharmacologic Options for Blood Pressure Lowering in Acute Stroke

Labetalol 10­20 mg IV over 1­2 minutes, may repeat IIb C­EO

Nicardipine 5 mg/hr IV, titrate up by 2.5 mg/hr every 5­15 minutes, maximum 15 mg/hr
Clevidipine 1­2 mg/hr IV, titrate by doubling the dose every 2­5 minutes, maximum 21 mg/hr
Other agents to consider: hydralazine, enalaprilat, nitroprusside IV infusion, labetalol IV infusion

ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; GLP1, glucagon­like peptide 1; HbA1c, hemoglobin A1c; ICH, intracerebral hemorrhage; INR,
international normalized ratio; IV, intravenous; LDL, low­density lipoprotein; NIHSS, National Institutes of Health Stroke Scale.

Data from References 6 and 7.

aClass (strength) of recommendation : I, strong; IIa, moderate; IIb, weak; III, no benefit (moderate); 3, harm (strong).

b Level (quality) of evidence: A, high­quality evidence from more than 1 randomized clinical trial, meta­analyses of high­quality randomized clinical trials, or one or

more randomized clinical trials corroborated by high­quality registry studies; B­R (randomized), moderate­quality evidence from one or more randomized clinical
trials or meta­analyses of moderate­quality randomized clinical trials; B­NR (nonrandomized), moderate­quality evidence from one or more well­designed, well­
executed nonrandomized studies, observational studies, or registry studies or meta­analyses of such studies; C­LD (limited data), randomized or nonrandomized
observational or registry studies with limitations or design or execution, meta­analyses of such studies, or physiological or mechanistic studies in human subjects; C­
EO (expert opinion), consensus of expert opinion based on clinical experience.

Downloaded 2022­10­24 2:51 P Your IP is 41.233.255.202

cVery high risk of future ASCVD events includes a history of multiple major ASCVD events or 1 major ASCVD event and multiple high­risk conditions. Major ASCVD
Chapter 39: Stroke, Melody Ryan; Melissa Nestor Page 12 / 35
©2022
eventsMcGraw Hill.
are history All Rights
of ischemic Reserved.
stroke, Termssyndrome
acute coronary of Use •within
Privacy
thePolicy
past 12•months,
Noticehistory
• Accessibility
of myocardial infarction, symptomatic peripheral arterial disease.
High­risk conditions include: age ≥65 years; heterozygous familial hypercholesterolemia; history of coronary artery bypass surgery or percutaneous coronary
intervention outside of the major ASCVD events; diabetes; hypertension; chronic kidney disease; current smoking.
 more randomized clinical trials corroborated by high­quality registry studies; B­R (randomized), moderate­quality evidence from one or more randomized clinical
Birzeit well­
trials or meta­analyses of moderate­quality randomized clinical trials; B­NR (nonrandomized), moderate­quality evidence from one or more well­designed, University
Access Provided by:
executed nonrandomized studies, observational studies, or registry studies or meta­analyses of such studies; C­LD (limited data), randomized or nonrandomized
observational or registry studies with limitations or design or execution, meta­analyses of such studies, or physiological or mechanistic studies in human subjects; C­
EO (expert opinion), consensus of expert opinion based on clinical experience.

cVery high risk of future ASCVD events includes a history of multiple major ASCVD events or 1 major ASCVD event and multiple high­risk conditions. Major ASCVD

events are history of ischemic stroke, acute coronary syndrome within the past 12 months, history of myocardial infarction, symptomatic peripheral arterial disease.
High­risk conditions include: age ≥65 years; heterozygous familial hypercholesterolemia; history of coronary artery bypass surgery or percutaneous coronary
intervention outside of the major ASCVD events; diabetes; hypertension; chronic kidney disease; current smoking.

Once the patient is out of the hyperacute phase (e.g. first 24 hours), management is focused on preventing worsening of stroke, minimizing
complications, and secondary prevention. The acute phase of the stroke includes the first week after the event.4

Nonpharmacologic Therapy

Ischemic Stroke

To reperfuse ischemic brain tissue, endovascular intervention and thrombectomy is recommended by the American Heart Association
(AHA)/American Stroke Association (ASA) since 2015 based on data from several clinical trials.7 Thrombectomy is strongly recommended for patients
with anterior circulation arterial occlusion in the ICA or the M1 segment of the MCA who are within 6 hours of symptom onset and may be considered in
select patients within 6 to 24 hours of symptom onset. Patients with ICA and M1 MCA arterial occlusions and symptom onset within 24 hours may be
candidates for endovascular intervention if imaging studies suggest a significant area of salvageable penumbra is present. The benefit of mechanical
thrombectomy is less clear in patients with posterior circulation occlusions and should be considered in a case­by­case basis.7 The availability of this
mechanical intervention for stroke has greatly increased the importance of early vascular diagnostic imaging followed by rapid transfer to centiers with
interventional capabilities and escalation of care in patients with these emergent large vessel occlusions.

Large infarcts of the MCA are often devastating and, in patients without recanalization via pharmacologic or mechanical intervention, are associated
with high rates of morbidity and mortality. 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. In patients under 60 years of age with unilateral MCA
infarcts and significant cerebral edema, surgical intervention with decompressive craniectomy has been shown to reduce mortality by almost 50% and
improve favorable neurologic outcomes at one year. This surgical intervention can be considered for patients over the age of 60 but the likelihood of
favorable neurologic outcome is less robust. In patients with cerebellar infarction and significant swelling, surgical decompression can be lifesaving.
For all ischemic stroke patients coordinated care with a multidisciplinary approach to assessment and early rehabilitation is effective in reducing
overall disability due to stroke.7

For the secondary prevention of ischemic stroke, carotid endarterectomy of an ulcerated and/or stenotic carotid artery is a very effective way to
reduce stroke incidence and recurrence in patients with 70% to 99% stenosis if performed in centers with low operative morbidity and mortality.8
Carotid stenting is a less invasive alternative that can be effective in reducing recurrent stroke risk when combined with aspirin and clopidogrel
therapy.8 However, it is associated with a higher periprocedural stroke rate.8

A patent foramen ovale (PFO) occurs when the septum between the right and left atria fails to close after birth. A PFO is present in 20% to 25% of
adults; but in patients with stroke from unknown causes, 40% to 50% have a PFO.9 The PFO can be closed surgically. People who benefit most from this
surgery are 18 to 60 years of age with nonlacunar ischemic strokes of undetermined cause.8

Other nonpharmacological approaches for secondary stroke prevention include diet modification, exercise, smoking cessation, avoidance of
environmental tobacco smoke, moderation of alcohol consumption, and avoidance of stimulants such as amphetamines and cocaine. A
Mediterranean­type diet and, in patients with hypertension, reducing sodium intake is recommended. Exercise plans should take any mobility
considerations into account. Alcohol consumption should be no greater than two drinks per day for men or one drink per day for women.8

Hemorrhagic Stroke

SAH often arises from a ruptured intracranial aneurysm or AVM and intervention as early as possible with either surgical clipping or endovascular
coiling of the vascular anomaly reduces the risk of rebleeding and improves mortality.6 For patients with cerebellar ICH and neurologic deterioration,
brainstem compression, and/or hydrocephalus from ventricular obstruction, early surgical intervention and hematoma removal is recommended. For
patients with cerebral ICH, the usefulness of surgical hematoma evacuation or use of minimally­invasive clot evacuation are not well established.
Downloaded 2022­10­24 2:51 P Your IP is 41.233.255.202
Ventricular drainage with an extraventricular drain (EVD) is reasonable in patients with hydrocephalus causing decreased consciousness.6Page 13 / 35
Chapter 39: Stroke, Melody Ryan; Melissa Nestor
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
Temperature Management
Hemorrhagic Stroke
Birzeit University
SAH often arises from a ruptured intracranial aneurysm or AVM and intervention as early as possible with either surgical clipping or endovascular
Access Provided by:

coiling of the vascular anomaly reduces the risk of rebleeding and improves mortality.6 For patients with cerebellar ICH and neurologic deterioration,
brainstem compression, and/or hydrocephalus from ventricular obstruction, early surgical intervention and hematoma removal is recommended. For
patients with cerebral ICH, the usefulness of surgical hematoma evacuation or use of minimally­invasive clot evacuation are not well established.
Ventricular drainage with an extraventricular drain (EVD) is reasonable in patients with hydrocephalus causing decreased consciousness.6

Temperature Management

Fever worsens outcomes in patients with both hemorrhagic and ischemic stroke types. 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; it should be done only in a controlled, clinical trial setting.6,7

Pharmacologic Therapy

Ischemic Stroke

Acute Treatment

The stroke council of the ASA has created and published guidelines that address the management of acute ischemic stroke.7 For acute treatment, the
only two pharmacologic agents with class I recommendations are alteplase initiated within 4.5 hours of stroke onset and aspirin started within 24 to 48
hours of stroke onset (Table 39­3).7

TABLE 39­3
Recommendations for Pharmacotherapy of Ischemic Stroke

Acute Treatment of Ischemic Stroke7

Level
Class (Strength) of (Quality)
Recommendation
Recommendationa of
Evidenceb

Alteplase 0.9 mg/kg IV (maximum 90 mg), 10% as a bolus with the remainder given over 1 hour in selected patients

Within 3 hours of onset I A

Between 3 and 4.5 hours of onset I B­R

Tenecteplase 0.25 mg/kg IV bolus (maximum 25 mg) may be a reasonable alternative to alteplase for patients who IIb B­R
are also eligible to undergo mechanical thrombectomy

Tenecteplase 0.4 mg/kg IV bolus (maximum 40 mg) has not been proved to be superior or non­inferior to alteplase IIb B­R
but may be considered as an alternative to alteplase in patients with minor neurological impairment and no major
intracranial occlusion

Aspirin 160­325 mg daily started within 48 hours of onset I A

Aspirin 81 mg daily and clopidogrel 75 mg daily for 21 days may be effective in reducing recurrent stroke in patients I A
who do not receive IV alteplase and present with minor, non­cardioembolic stroke (NIHSS ≤ 3)

Ticagrelor is not recommended over aspirin for treatment of patients with minor acute stroke III B­R

Acute Treatment of Spontaneous Intracerebral Hemorrhage6

Downloaded 2022­10­24 2:51 P Your IP is 41.233.255.202
Chapter 39: Stroke, Melody Ryan; Melissa Nestor
Patients with a severe coagulation factor deficiency or severe thrombocytopenia should receive appropriate factor I
Page 14 / 35
C
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
replacement therapy or platelets
 Aspirin 81 mg daily and clopidogrel 75 mg daily for 21 days may be effective in reducing recurrent stroke in patients I A
who do not receive IV alteplase and present with minor, non­cardioembolic stroke (NIHSS ≤ 3)
Birzeit University
Access Provided by:

Ticagrelor is not recommended over aspirin for treatment of patients with minor acute stroke III B­R

Acute Treatment of Spontaneous Intracerebral Hemorrhage6

Patients with a severe coagulation factor deficiency or severe thrombocytopenia should receive appropriate factor I C
replacement therapy or platelets

Prophylactic antiseizure medication is not recommended III B

Secondary Prevention of Ischemic Stroke

Stroke Etiology Recommendation Class (Strength) of Level

Recommendationa (Quality)
of

Evidenceb

Noncardioembolic Antiplatelet therapy7

Aspirin 50­325 mg daily I A

Aspirin 25 mg + extended­release I A
dipyridamole 200 mg twice daily

Clopidogrel 75 mg daily I A

Cardioembolic (especially atrial fibrillation) Anticoagulant therapy7

Vitamin K antagonist (warfarin) (INR = 2­3) I A

Apixaban 5 mg twice daily I A

Dabigatran 150 mg twice daily I A

Edoxaban 60 mg daily I A

Rivaroxaban 20 mg daily I A

Atrial fibrillation without moderate to severe mitral stenosis or Apixaban, dabigatran, endoxaban, or I B­R
a mechanical heart valve rivaroxaban is preferred over warfarin

Risk Factor Recommendation1 0 Class (Strength) of Level

Recommendationa (Quality)
of

Evidenceb

LDL cholesterol > 100 mg/dL (2.59 mmol/L) with no known Atorvastatin 80 mg daily I A
coronary heart disease, and no major cardiac sources of
embolism

Downloaded 2022­10­24 2:51 P Your IP is 41.233.255.202

Patients with atherosclerotic disease Statins and ezetimibe, if needed; goal LDL I A 15 / 35
Chapter 39: Stroke, Melody Ryan; Melissa Nestor Page
cholesterol
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • <70 mg/dL
Notice (1.81 mmol/L)
• Accessibility

Very high risk (stroke + another major ASCVD or stroke + Proprotein convertase subtilisin/kexin type 9 IIa B­NR
 Evidenceb
Birzeit University
LDL cholesterol > 100 mg/dL (2.59 mmol/L) with no known Atorvastatin 80 mg daily I Access A
Provided by:

coronary heart disease, and no major cardiac sources of

embolism

Patients with atherosclerotic disease Statins and ezetimibe, if needed; goal LDL I A
cholesterol <70 mg/dL (1.81 mmol/L)

Very high risk (stroke + another major ASCVD or stroke + Proprotein convertase subtilisin/kexin type 9 IIa B­NR

multiple high­risk conditions)c already taking statins at inhibitor therapy

maximally tolerated dose and ezetimibe, but who still have

LDL­cholesterol >70 mg/dL (1.81 mmol/L)

Fasting triglycerides 135­499 mg/dL (1.53 ­ 5.64 mmol/L) and Icoaspent ethyl 2 g twice daily IIa B­R
LDL cholesterol 41­100 mg/dL (1.06­2.59 mmol/L) who are on
moderate­ or high­intensity statin therapy, with HbA1c <10%
(86 mmol/mol), and no history of pancreatitis, atrial
fibrillation, or severe heart failure

Fasting triglycerides ≥ 500 mg/dL (5.65 mmol/L) Identify and address causes of IIa B­NR
hypertriglyceridemia; implement a very low­fat
diet, avoid refined carbohydrates and alcohol;
omega­3 fatty acids; fibrate therapy, if needed
to prevent acute pancreatitis

BP >130/80 BP reduction, goal <130/80 mm Hg I B­R

Patients who smoke Smoking cessation with or without drug therapy I A

Men who drink > 2 alcoholic drinks per day or women who Reduce or eliminate alcohol consumption I B­NR
drink > 1 alcoholic drink per day

Patients who use stimulants and patients with infective Cessation of use of substance I C­EO
endocarditis in the context of intravenous drug use

Diabetes ­ treatment goal Goal HbA1c ≤7% (53 mmol/mol) I A

Diabetes ­ drug therapy selection Treatment with glucose­lowering agents with I B­R
proven cardiovascular benefit (metformin +
GLP1 receptor agonist therapy or sodium­
glucose cotransporter 2 inhibitor) regardless of
baseline HbA1C

Prediabetes, particularly with BMI ≥35 kg/m2, <60 years, Metformin 850 mg twice daily IIb B­R

women with a history of gestational diabetes

aClass (strength) of recommendation : I, strong; IIa, moderate; IIb, weak; III, no benefit (moderate); 3, harm (strong).

b Level (quality) of evidence: A, high­quality evidence from more than 1 randomized clinical trial, meta­analyses of high­quality randomized clinical trials, or one or

more randomized clinical trials corroborated by high­quality registry studies; B­R (randomized), moderate­quality evidence from one or more randomized clinical
trials or meta­analyses of moderate­quality randomized clinical trials; B­NR (nonrandomized), moderate­quality evidence from one or more well­designed, well­
executed nonrandomized studies, observational studies, or registry studies or meta­analyses of such studies; C­LD (limited data), randomized or nonrandomized
observational or registry studies with limitations or design or execution, meta­analyses of such studies, or physiological or mechanistic studies in human subjects; C­
EO (expert opinion), consensus of expert opinion based on clinical experience.
Downloaded 2022­10­24 2:51 P Your IP is 41.233.255.202
cVery high risk of future ASCVD events includes a history of multiple major ASCVD events or 1 major ASCVD event and multiple high­risk conditions. Major ASCVD
Chapter 39: Stroke, Melody Ryan; Melissa Nestor Page 16 / 35
©2022
eventsMcGraw Hill.
are history All Rights
of ischemic Reserved.
stroke, Termssyndrome
acute coronary of Use •within
Privacy
thePolicy
past 12•months,
Noticehistory
• Accessibility
of myocardial infarction, symptomatic peripheral arterial disease.
High­risk conditions include: age ≥65 years; heterozygous familial hypercholesterolemia; history of coronary artery bypass surgery or percutaneous coronary
intervention outside of the major ASCVD events; diabetes; hypertension; chronic kidney disease; current smoking.
 more randomized clinical trials corroborated by high­quality registry studies; B­R (randomized), moderate­quality evidence from one or more randomized clinical
Birzeit University
trials or meta­analyses of moderate­quality randomized clinical trials; B­NR (nonrandomized), moderate­quality evidence from one or more well­designed, well­
Access Provided by:
executed nonrandomized studies, observational studies, or registry studies or meta­analyses of such studies; C­LD (limited data), randomized or nonrandomized
observational or registry studies with limitations or design or execution, meta­analyses of such studies, or physiological or mechanistic studies in human subjects; C­
EO (expert opinion), consensus of expert opinion based on clinical experience.

cVery high risk of future ASCVD events includes a history of multiple major ASCVD events or 1 major ASCVD event and multiple high­risk conditions. Major ASCVD

events are history of ischemic stroke, acute coronary syndrome within the past 12 months, history of myocardial infarction, symptomatic peripheral arterial disease.
High­risk conditions include: age ≥65 years; heterozygous familial hypercholesterolemia; history of coronary artery bypass surgery or percutaneous coronary
intervention outside of the major ASCVD events; diabetes; hypertension; chronic kidney disease; current smoking.

ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; GLP1, glucagon­like peptide 1; HbA1c, hemoglobin A1c; ICH, intracerebral hemorrhage; INR,
international normalized ratio; IV, intravenous; LDL, low­density lipoprotein; NIHSS, National Institutes of Health Stroke Scale.

Alteplase
Early pharmacologic reperfusion (initiated less than 4.5 hours from symptom onset) with IV alteplase has been a mainstay of acute pharmacologic
treatment to improve functional ability after ischemic stroke as compared to no intervention.7 Alteplase, or recombinant tissue plasminogen activator
(rt­PA), is a fibrinolytic agent that exhibits a moderate binding preference for fibrin and facilitates the conversion of plasminogen to plasmin, leading to
degradation of fibrin clots. Alteplase has a short half­life (approximately 4 minutes). The total dose for acute ischemic stroke is 0.9 mg/kg (maximum 90
mg), 10% administered as an intravenous (IV) bolus over 1 minute, and the remaining 90% given as an IV infusion over 60 minutes.7

The first large trial demonstrating the effectiveness of IV alteplase in the treatment of ischemic stroke was published in 1995. A subsequent study
demonstrated improved functional outcome at 3 months in patients with acute ischemic stroke treated with alteplase between 3 and 4.5 hours of
stroke symptom onset when compared with placebo (52.4% vs 45.2%).7 Based on these data, the AHA/ASA guidelines extended the window for
alteplase from 3 hours to up to 4.5 hours from symptom onset. However, there may be diminished benefit of alteplase in patients presenting within 3
to 4.5 hours from symptom onset and severe stroke (NIHSS>25 or evidence of more than one­third of MCA territory infarct on initial imaging).7
Consequently, delays in alteplase therapy should be minimized and early administration prioritized since this approach is associated with improved
outcomes.

Alteplase use is associated with a high risk for bleeding, including ICH. Therefore, adherence to the guideline­recommended protocol is essential for
achieving a positive outcome and minimizing the risk. This protocol can be summarized as (a) stroke team activation, (b) brain imaging study (eg, CT
scan), (c) treatment as early as possible within 4.5 hours of symptom onset, (d) meeting inclusion and exclusion criteria (TABLE 39­4), (e)
administration of alteplase 0.9 mg/kg total dose (maximum dose of 90 mg), 10% given as a bolus over 1 minute and the remaining 90% given as an IV
infusion over 1 hour, (f) avoidance of antithrombotic therapy (anticoagulant or antiplatelet) for 24 hours after alteplase, and (g) close patient
monitoring for BP, 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.7

TABLE 39­4
Inclusion and Exclusion Criteria for Alteplase Use in Acute Ischemic Stroke

Inclusion Criteria

Age ≥18 years

Clinical diagnosis of ischemic stroke with neurologic deficit
Time of symptom onset well established to be <4.5 hours from treatment initiation

Contraindications

History of intracranial hemorrhageHistory of ischemic stroke within prior 3 monthsSymptoms/Imaging consistent with subarachnoid hemorrhage or
acute intracerebral hemorrhage
Current use of direct thrombin inhibitors or direct factor Xa inhibitors in prior 48 hours
Use of treatment­dose low molecular weight heparin in prior 24 hours
Infective endocarditis
Intra­axial, intracranial neoplasm
Aortic arch dissection
Downloaded 2022­10­24
Active 2:51 PorYour
internal bleeding IP is 41.233.255.202
coagulopathy (platelets <100,000/mm3 [100 × 109/L], INR>1.7, aPTT>40s, PT>15s)
Chapter 39: Stroke, Melody Ryan; Melissa Nestor Page 17 / 35
Severe head trauma in prior 3 months
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
Gastrointestinal malignancy or bleeding within prior 21 days
monitoring for BP, 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.7 Birzeit University
Access Provided by:
TABLE 39­4
Inclusion and Exclusion Criteria for Alteplase Use in Acute Ischemic Stroke

Inclusion Criteria

Age ≥18 years

Clinical diagnosis of ischemic stroke with neurologic deficit
Time of symptom onset well established to be <4.5 hours from treatment initiation

Contraindications

History of intracranial hemorrhageHistory of ischemic stroke within prior 3 monthsSymptoms/Imaging consistent with subarachnoid hemorrhage or
acute intracerebral hemorrhage
Current use of direct thrombin inhibitors or direct factor Xa inhibitors in prior 48 hours
Use of treatment­dose low molecular weight heparin in prior 24 hours
Infective endocarditis
Intra­axial, intracranial neoplasm
Aortic arch dissection

Active internal bleeding or coagulopathy (platelets <100,000/mm3 [100 × 109/L], INR>1.7, aPTT>40s, PT>15s)
Severe head trauma in prior 3 months
Gastrointestinal malignancy or bleeding within prior 21 days

Warnings/Use Clinical Judgment

Unruptured/unsecured AVM or aneurysm >10 mm

Major surgery or nonhead trauma
History of bleeding diathesis
Extensive regions of clear hypoattenuation on initial CT scan

aPTT, activated partial thromboplastin time; AVM, arteriovenous malformation; CT, computed tomography; INR, international normalized ratio; PT; prothrombin
time.

Data from Reference 7.

Tenecteplase
Tenecteplase is a modified form of tissue plasminogen activator with protein substitutions that yield a higher degree of fibrin specificity and a longer
half­life than alteplase. Unlike alteplase, tenecteplase can be administered as a single, rapid IV bolus dose. While tenecteplase is FDA­approved for the
management of patients with acute ST­elevation myocardial infarction, use for ischemic stroke remains off­label. Tenecteplase has been studied in a
variety of acute ischemic stroke populations and is specifically mentioned in the 2019 update to the AHA/ASA guidelines. Tenecteplase 0.4 mg/kg
(maximum 40 mg), given as an IV bolus, may be considered as an alternative to alteplase for patients with ischemic stroke and mild neurologic
impairment (class IIb recommendation).7 It may also be reasonable to choose an IV bolus of tenecteplase 0.25 mg/kg (maximum 25 mg) over alteplase
for patients who are also eligible to undergo mechanical thrombectomy (class IIb recommendation).7 Ongoing studies may further define the role of
tenecteplase in patients with acute ischemic, identify the optimal dose, and support stronger recommendations in the future.

Aspirin
Early aspirin therapy, within 24 to 48 hours from symptom onset, should be given to patients with acute ischemic stroke in the absence of aspirin
allergy or other contraindications. For patients receiving alteplase, aspirin and other antithrombotics are generally held for 24 hours after alteplase
administration to reduce the risk of hemorrhage.7

Early use of aspirin in ischemic stroke patients is recommended by the AHA/ASA guidelines to reduce the long­term risk of death and disability.7 Data
are limited to describe acute use of non­aspirin antiplatelet agents in the acute stroke phase, apart from combination therapy regimens described
Downloaded 2022­10­24 2:51 P Your IP is 41.233.255.202
below. However, using an alternative antiplatelet agent in patients with acute ischemic stroke who have a severe allergy or contraindication to aspirin
Chapter 39: Stroke, Melody Ryan; Melissa Nestor Page 18 / 35
©2022
may be McGraw 7
Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
reasonable.

Aspirin exerts its antiplatelet effect by irreversibly inhibiting cyclooxygenase (COX)­1, which, in platelets, prevents the conversion of arachidonic acid to
Early aspirin therapy, within 24 to 48 hours from symptom onset, should be given to patients with acute ischemic stroke in the absence of aspirin
Birzeit
allergy or other contraindications. For patients receiving alteplase, aspirin and other antithrombotics are generally held for 24 hours after University
alteplase
administration to reduce the risk of hemorrhage.7
Access Provided by:

Early use of aspirin in ischemic stroke patients is recommended by the AHA/ASA guidelines to reduce the long­term risk of death and disability.7 Data
are limited to describe acute use of non­aspirin antiplatelet agents in the acute stroke phase, apart from combination therapy regimens described
below. However, using an alternative antiplatelet agent in patients with acute ischemic stroke who have a severe allergy or contraindication to aspirin
may be reasonable.7

Aspirin exerts its antiplatelet effect by irreversibly inhibiting cyclooxygenase (COX)­1, which, in platelets, prevents the conversion of arachidonic acid to
thromboxane A2 (TXA2), a powerful vasoconstrictor and stimulator of platelet aggregation. The onset of the antiplatelet effect of aspirin is less than 60
minutes, and platelets remain impaired for their life span (5­7 days) after exposure to aspirin.11 Aspirin also inhibits COX­2 in a dose­dependent
manner, leading to decreased prostacyclin (PGI2) activity in vascular smooth muscle.12 There is probably a point at which lower doses of aspirin do not
completely block TXA2, and studies indicate that the lowest effective dose may be in the range of 75 mg/day.12 Upper gastrointestinal (GI) discomfort
and bleeding are the most common adverse effects of aspirin and have been shown to be dose­related. The risk of major bleeding is 43% higher in
patients treated with aspirin compared to patients not receiving aspirin. The risk of bleeding is dose­dependent and increases with increasing age;
therefore, the upper limit of the aspirin dose is between 300 mg and 325 mg.7

Some patients either have or develop high on­treatment platelet reactivity (“aspirin resistance”) and can require higher doses or twice daily dosing to
achieve the desired antiplatelet effect.13 Several factors contribute to this effect, including aging, diabetes, hyperlipidemia, smoking, chronic kidney
disease, and drug­drug interactions (eg, non­steroidal anti­inflammatory drugs).14 Genetic polymorphisms, including those influencing activity of COX­
1, COX­2, glycoprotein IIb/IIIa receptors, and adenosine diphosphate (ADP) receptors, may contribute to aspirin resistance.15 Despite the growing
evidence linking aspirin resistance to worse outcomes in patients with stroke, routine testing for aspirin resistance is not recommended.

Blood Pressure Management

In general, patients with acute ischemic stroke commonly present with elevated or normal BP. However, hypotension and hypovolemia, if present,
should be corrected to maintain systemic perfusion and end organ function. For patients with elevated BP who are otherwise eligible for alteplase, the
treatment of hypertension to a goal SBP of less than 185 mm Hg and diastolic BP 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 IV thrombolytic therapy or endovascular intervention, “permissive hypertension”, allowing BP to rise as high
as 220/120 mm Hg for the first 48 to 72 hours, is often implemented as early initiation of antihypertensive therapy does not prevent death or
dependency. For patients with comorbid conditions requiring BP lowering, a reduction of 15% is reasonable. See Table 39­3 for a summary of these
recommendations and pharmacotherapeutic options.7 When treating hypertension in acute ischemic stroke, it is typical to use IV drugs with a faster
time to onset and ability to titrate to patient response. Calcium channel blocker infusions, such as nicardipine and clevidipine, are often preferred.
Labetalol can be administered as an IV bolus dose or as a continuous infusion. In patients with refractory hypertension, there may be a role for last­line
agents such as sodium nitroprusside to achieve BP goals.

Therapeutic Anticoagulation
Use of therapeutic anticoagulation (eg, unfractionated heparin or low­molecular­weight heparin) is not routinely recommended in the early phase of
acute ischemic stroke treatment. The clinical benefit of therapeutic anticoagulation in the setting of nonocclusive intraluminal thrombus in acute
stroke is limited. Restricted use on a case­by­case basis or in a clinical trial setting may be considered. Anticoagulation for non­stroke indications (eg,
venous thromboembolism prophylaxis or treatment) must be weighed against the risk of ICH conversion in patients with acute ischemic stroke.7
Patients with immobility after stroke should be receive either mechanical or pharmacologic venous thromboembolism prophylaxis. Drug selection,
dosing, and timing of pharmacologic venous thromboembolism prophylaxis will depend on patient factors and conconimitant treatment for stroke.

Secondary Prevention

Antiplatelet therapy is the cornerstone of antithrombotic therapy for the secondary prevention of ischemic stroke and should be used in
noncardioembolic strokes. Aspirin, extended­release dipyridamole plus aspirin, clopidogrel, and ticagrelor are all recommended for secondary stroke
prevention.4 In patients with atrial fibrillation, oral anticoagulation with apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin is recommended for
secondary stroke prevention.4 Other pharmacotherapy recommended for secondary prevention of stroke includes treatment of hypertension and
statin therapy. Current recommendations regarding the acute treatment and secondary prevention of stroke are given in Table 39­2.

Antiplatelet Agents
All patients who have had an acute ischemic stroke or TIA should receive long­term antithrombotic therapy for secondary prevention.4 In patients with
Downloaded 2022­10­24
noncardioembolic 2:51will
stroke, this P Your IP isform
be some 41.233.255.202
of antiplatelet therapy. In a comprehensive meta­analysis, antiplatelet therapy reduced the odds of a
Chapter 39: Stroke, Melody Ryan; Melissa Nestor Page 19 / 35
16 While aspirin is the antiplatelet agent with the most data supporting its use, there is
second stroke byHill.
©2022 McGraw 16%AlltoRights
41% inReserved.
patients withTerms
previous stroke.
of Use • Privacy Policy • Notice • Accessibility
also evidence to support using clopidogrel and the combination product extended­release dipyridamole plus aspirin as alternative first­line agents for
secondary stroke prevention.8 For patients already taking aspirin at the time of a noncardioemoblic ischemic stroke or TIA, there is no evidence that
prevention.4 In patients with atrial fibrillation, oral anticoagulation with apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin is recommended for
Birzeit University
secondary stroke prevention.4 Other pharmacotherapy recommended for secondary prevention of stroke includes treatment of hypertension and
Access Provided by:
statin therapy. Current recommendations regarding the acute treatment and secondary prevention of stroke are given in Table 39­2.

Antiplatelet Agents
All patients who have had an acute ischemic stroke or TIA should receive long­term antithrombotic therapy for secondary prevention.4 In patients with
noncardioembolic stroke, this will be some form of antiplatelet therapy. In a comprehensive meta­analysis, antiplatelet therapy reduced the odds of a
second stroke by 16% to 41% in patients with previous stroke.16 While aspirin is the antiplatelet agent with the most data supporting its use, there is
also evidence to support using clopidogrel and the combination product extended­release dipyridamole plus aspirin as alternative first­line agents for
secondary stroke prevention.8 For patients already taking aspirin at the time of a noncardioemoblic ischemic stroke or TIA, there is no evidence that
increasing the dose of aspirin is more effective at preventing additional strokes.8

Clopidogrel
Clopidogrel exerts its antiplatelet effect by inhibiting the ADP pathway of platelet aggregation through antagonism of the purinergic receptor P2Y, G­
protein coupled 12 (P2Y12) receptor.12,17 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. In the absence of a loading dose, the maximal antiplatelet effect is
delayed for 3 to 7 days.

Clopidogrel is a prodrug and requires activation by the cytochrome P450 isoenzyme 2C19 (CYP2C19) to achieve its antiplatelet effect. There are
polymorphisms of various alleles encoding for this enzyme, with *1 being the wild type, *17 leading to increased metabolism, and *2 and *3 causing
decreased metabolism. Thus, individuals with one copy of *2 or *3 are classified as intermediate metabolizers and those with two copies of *2 or *3 or
one copy of each (*2/*3) are termed poor metabolizers, leading to diminished antiplatelet activity.18 Poor metabolizers are found in about 2% of
Caucasians, 4% of African Americans, and 14% of Chinese.18 Consequently, the Clinical Pharmacogenetics Implementation Consortium and the Dutch
Pharmacogenetics Working Group of the Royal Dutch Association for the Advancement of Pharmacy both suggest pharmacogenetic testing prior to
using clopidogrel.18 However, current AHA/ASA guidelines for acute treatment of stroke do not suggest doing so.8 Medications that inhibit CYP2C19
may also reduce the antiplatelet activity of clopidogrel. Omeprazole and esomeprazole both inhibit CYP2C19 and their use should be avoided in
patients taking clopidogrel. Opioids slow gastric emptying, delaying and decreasing absorption, leading to reduced antiplatelet activity and,
potentially, decreased efficacy.19

In a study of patients with atherothrombotic disorders (eg, ischemic stroke, myocardial infarction, or peripheral arterial disease), clopidogrel was
slightly more effective than aspirin in preventing vascular events and had a similar incidence of adverse effects.20 The tolerability of clopidogrel 75
mg/day is at least as good as medium­dose (325 mg/day) aspirin and there is less GI bleeding.20 Clopidogrel is associated with an increased risk of
diarrhea and rash, but discontinuation rates due to adverse effects are similar to those with aspirin 325 mg/day (5.3% and 6%, respectively).20

Extended­Release Dipyridamole Plus Aspirin

Dipyridamole, in high doses, is thought to inhibit phosphodiesterase, increasing intracellular cyclic adenosine monophosphate (cAMP) and cyclic
guanosine monophosphate (cGMP), leading to inhibition of platelet activation.12 Early studies of the role of dipyridamole in stroke prevention failed to
show a benefit over aspirin alone. However, 25% of the patients who received combination dipyridamole and aspirin discontinued the therapy early,
many due to adverse drug reactions. The discontinuation due to headache was more than threefold higher (10%) than the aspirin­alone group (3%).21
Another study demonstrated similar efficacy in preventing recurrent stroke between the combination of extended­release dipyridamole and aspirin
and clopidogrel.22 However, clopidogrel was better tolerated with less bleeding and headache. Despite carefully educating and coaching patients on
managing headache, discontinuation due to headache was six times higher in the extended­release dipyridamole plus aspirin group (5.9% vs 0.9%)
compared to clopidogrel.22 The extended­release formulation of dipyridamole is important in that it allows twice­daily administration. The use of
immediate­release dipyridamole in combination with regular aspirin, in order to reduce costs, is unproven and should be discouraged.

Ticagrelor
Ticagrelor is a direct­acting P2Y12 receptor inhibitor.17 Ticagrelor (loading dose of 180 mg then 90 mg twice daily for 90 days) was compared to aspirin

(300 mg loading dose then 100 mg daily 90 days) in a large clinical trial of patients with noncardioembolic stroke not treated with alteplase.23 Ticagrelor
did not demonstrate superiority to aspirin in this trial.23 However, in a subgroup analysis of patients with an atherosclerotic cause of stroke, there was
a 32% lower risk of secondary stroke within 90 days in patients treated with ticagrelor.24 Despite this subgroup analysis, ticagrelor is not FDA­approved
for secondary stroke prevention.

Dual Antiplatelet Therapy

The combination of two or more antiplatelet medications for secondary stroke prevention may be an option for select patients (Table 39­5). The
Downloaded 2022­10­24 2:51 P Your IP is 41.233.255.202
combination of clopidogrel and aspirin has been the most studied dual antiplatelet strategy. A systematic review determined that short­term use
20of/ 35
Chapter 39: Stroke, Melody Ryan; Melissa Nestor Page
dual antiplatelet therapy (≤90 days) was associated with a significantly lower risk of recurrent
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility stroke without an accompanying risk of major
bleeding.25 However, in longer­term studies (>90 days), the dual therapy was not associated with a reduced number of strokes but did increase the risk
of major bleeding. Therefore, use of dual antiplatelet therapy with aspirin and clopidogrel for longer than 90 days is not recommended.8
did not demonstrate superiority to aspirin in this trial.23 However, in a subgroup analysis of patients with an atherosclerotic cause of stroke, there was
Birzeit University
a 32% lower risk of secondary stroke within 90 days in patients treated with ticagrelor.24 Despite this subgroup analysis, ticagrelor is not FDA­approved
Access Provided by:
for secondary stroke prevention.

Dual Antiplatelet Therapy

The combination of two or more antiplatelet medications for secondary stroke prevention may be an option for select patients (Table 39­5). The
combination of clopidogrel and aspirin has been the most studied dual antiplatelet strategy. A systematic review determined that short­term use of
dual antiplatelet therapy (≤90 days) was associated with a significantly lower risk of recurrent stroke without an accompanying risk of major
bleeding.25 However, in longer­term studies (>90 days), the dual therapy was not associated with a reduced number of strokes but did increase the risk
of major bleeding. Therefore, use of dual antiplatelet therapy with aspirin and clopidogrel for longer than 90 days is not recommended.8

TABLE 39­5
Dual Antiplatelet Recommendations for Patients with Noncardioembolic Ischemic Stroke or TIA

Patient Sub­type Recommendation Class (Strength) of Level

Recommendationa (Quality)
of

Evidenceb

Minor stroke (NIHSS score ≤3)orhigh­risk TIA Aspirin and clopidogrel should be initiated within 7 days I A

(ABCD2 score ≥4)c (ideally within 12­24 hours). Continue for 21­90 days followed
by single agent antiplatelet therapy

Recent (<30 days) minor stroke or TIA Aspirin and clopidogrel 75 mg daily for up to 90 days followed IIa B­NR
attributable to 70­99% stenosis of a major by single agent antiplatelet therapy
intracranial artery

Recent (within 24 hours) minor stroke or high­risk Ticagrelor 90 mg twice a day may be added to aspirin for up IIb B­NR
TIA and concomitant ipsilateral >30% stenosis of to 30 days
a major intracranial artery

aClass (strength) of recommendation : I, strong; IIa, moderate; IIb, weak; III, no benefit (moderate); III, harm (strong).

b Level (quality) of evidence: A, high­quality evidence from more than 1 randomized clinical trial, meta­analyses of high­quality randomized clinical trials, or one or

more randomized clinical trials corroborated by high­quality registry studies; B­R (randomized), moderate­quality evidence from one or more randomized clinical
trials or meta­analyses of moderate­quality randomized clinical trials; B­NR (nonrandomized), moderate­quality evidence from one or more well­designed, well­
executed nonrandomized studies, observational studies, or registry studies or meta­analyses of such studies; C­LD (limited data), randomized or nonrandomized
observational or registry studies with limitations or design or execution, meta­analyses of such studies, or physiological or mechanistic studies in human subjects; C­
EO (expert opinion), consensus of expert opinion based on clinical experience.

cThe ABCD2 score is a clinical prediction rule used to determine the risk for stroke soon after a TIA. Score 1 point each for age ≥60 years, blood pressure ≥140/90 mm

Hg, speech disturbance, unilateral weakness, 10­59 minute duration, diabetes and 2 points for duration ≥ 60 minutes.

NIHSS, National Institutes of Health Stroke Scale; TIA, transient ischemic attack.

Data from Reference 8.

Ticagrelor (180 mg loading dose then 90 mg twice daily for 30 days) in combination with aspirin (300­325 mg loading dose then 75­100 mg daily) has
been compared to aspirin alone in patients with mild­moderate noncardioembolic stroke.26 Fewer patients in the dual therapy group had stroke or
death in the first 30 days compared to the aspirin­only group. However, the overall level of disability was not different between the groups, and the
incidence of severe bleeding, including ICH, was increased in the dual therapy group. A subgroup analysis of patients at higher risk for recurrent stroke
found rates of stroke and death were lower in the combination therapy group compared to aspirin alone while no difference in severe bleeding was
observed between the groups.27 Consequently, that the use of ticagrelor and aspirin together for secondary stroke prevention is only recommended
for patients with minor stroke or TIA with more than 30% stenosis of an ipsilateral major intercranial artery; combination therapy should be limited to
a duration of 30 days.8
Downloaded 2022­10­24 2:51 P Your IP is 41.233.255.202
Chapter 39: results
The positive Stroke,ofMelody Ryan; Melissa
dual antiplatelet Nestor
therapy
Page 21 / 35
led researchers to investigate triple antiplatelet therapy. One trial compared the combination of
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
aspirin, sustained­release dipyridamole, and clopidogrel to a “guideline group” which received either clopidogrel or aspirin and sustained­release
dipyridamole. This trial was stopped early because of a doubling of the risk of major bleeding in the triple therapy group. There was no difference in
death in the first 30 days compared to the aspirin­only group. However, the overall level of disability was not different between the groups, and the
incidence of severe bleeding, including ICH, was increased in the dual therapy group. A subgroup analysis of patients at higher risk forBirzeit
recurrent stroke
University
found rates of stroke and death were lower in the combination therapy group compared to aspirin alone while no difference in severe Access
bleeding was
Provided by:

observed between the groups.27 Consequently, that the use of ticagrelor and aspirin together for secondary stroke prevention is only recommended
for patients with minor stroke or TIA with more than 30% stenosis of an ipsilateral major intercranial artery; combination therapy should be limited to
a duration of 30 days.8

The positive results of dual antiplatelet therapy led researchers to investigate triple antiplatelet therapy. One trial compared the combination of
aspirin, sustained­release dipyridamole, and clopidogrel to a “guideline group” which received either clopidogrel or aspirin and sustained­release
dipyridamole. This trial was stopped early because of a doubling of the risk of major bleeding in the triple therapy group. There was no difference in
risk of recurrent stroke between the groups.28 Therefore, the use of triple antiplatelet therapy is not recommended.8

Oral Anticoagulants
Oral anticoagulation is the treatment of choice for the prevention of stroke in patients with atrial fibrillation and atrial flutter.4,29 Patients with atrial
fibrillation and a recent history of stroke or TIA are among the highest risk groups for stroke recurrence. However, there is a significant risk of bleeding
with anticoagulation. Thus, a stroke risk stratification tool known as CHA​2DS2­VASc has been developed to determine the patient’s risk of stroke (see

Chapter 40 “The Arrhythmias”). CHA2DS2­VASc scores greater than zero should receive oral anticoagulation therapy.4 Several risk stratification tools

have been developed to evaluate bleeding and determine bleeding risk. HAS­BLED is a simple tool that is widely used.30 A HAS­BLED score >2 indicates
a high risk for bleeding and should be accompanied by more intensive patient monitoring (Table 39­6).

TABLE 39­6
HAS­BLED Score for Assessing Bleeding Risk with Oral Anticoagulants

HAS­BLED Symbol Risk Factor Score

H Hypertension (SBP > 160 mm Hg) 1

A Abnormal renal or liver function 1

S Prior Stroke 1

B Prior major Bleeding or Bleeding predisposition 1

L Labile INRs (in therapeutic range < 60% of time) 1

E Elderly (age > 65 years) 1

D Drugs of abuse or excessive alcohol use 1

HAS­BLED score > 2 associated with clinically relevant and major bleeding.

SBP, systolic blood pressure, INR, international normalized ratio.

Data from References 4,30.

In patients with atrial fibrillation, adjusted­dose warfarin reduces stroke risk by 62% when compared to placebo and by 36% when compared to
aspirin.31 When using warfarin, targeting an international normalized ratio (INR) of 2 to 3 prevents stroke with the lowest bleeding risk; therefore, a
target INR of 2 to 3 is recommended for the secondary prevention of stroke.4,7,29 In settings of atrial fibrillation with mechanical heart valves or
moderate to severe mitral stenosis, warfarin should be used.8

Direct­acting oral anticoagulants (DOAC), including direct thrombin inhibitors (dabigatran) and direct factor Xa inhibitors (rivaroxaban, edoxaban, and
apixaban), have significant advantages over warfarin in terms of ease of dosing and less food and drug interactions. In addition, all four agents have
been shown to be as effective, and in some cases, superior to warfarin in reducing stroke risk with reduced rates of serious hemorrhage.29

Before using a DOAC, the patient’s renal function must be evaluated and the dose adjusted if significant renal impairment is present (TABLE 39­7).
Patients with creatinine
Downloaded 2022­10­24 clearance less than
2:51 P Your IP is15 mL/min (0.25 mL/s) or who require hemodialysis, either warfarin or apixaban are preferred.29
41.233.255.202
Chapter 39: Stroke,
Additionally, edoxaban Melody
shouldRyan; Melissa
not be given to patients with creatinine clearances above 95 mL/min because the risk of stroke is increasedPage
Nestor 22 / 35
compared
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
to warfarin.29 There is limited information on the use of these agents in patients with a body mass index over 40 kg/m2.32 However, emerging data
suggest that apixaban and rivaroxaban may be the best options for patients with a body weight over 120 kg or body mass index over 40 kg/m2.33
Direct­acting oral anticoagulants (DOAC), including direct thrombin inhibitors (dabigatran) and direct factor Xa inhibitors (rivaroxaban, edoxaban, and
Birzeit University
apixaban), have significant advantages over warfarin in terms of ease of dosing and less food and drug interactions. In addition, all four agents have
Access Provided by:
been shown to be as effective, and in some cases, superior to warfarin in reducing stroke risk with reduced rates of serious hemorrhage.29

Before using a DOAC, the patient’s renal function must be evaluated and the dose adjusted if significant renal impairment is present (TABLE 39­7).
Patients with creatinine clearance less than 15 mL/min (0.25 mL/s) or who require hemodialysis, either warfarin or apixaban are preferred.29
Additionally, edoxaban should not be given to patients with creatinine clearances above 95 mL/min because the risk of stroke is increased compared
to warfarin.29 There is limited information on the use of these agents in patients with a body mass index over 40 kg/m2.32 However, emerging data
suggest that apixaban and rivaroxaban may be the best options for patients with a body weight over 120 kg or body mass index over 40 kg/m2.33

TABLE 39­7
Direct­acting Oral Anticoagulant Dosing Adjustments Required for Renal Impairment.

Direct­acting Oral Usual Oral Dosing for Stroke

Dosing Adjustments
Anticoagulant Prevention in Atrial Fibrillation

Apixaban 5 mg twice daily 2.5 mg twice daily in patients with at least 2 high­risk characteristics below:Age ≥ 80
yearsBody weight ≤ 60 kgSerum creatinine ≥ 1.5 mg/dL (133 µmol/L)

Dabigatran 150 mg twice daily 75 mg orally twice daily if creatinine clearance 15­30 mL/min (0.25­0.50 mL/s)

Edoxaban 60 mg daily 30 mg orally daily if creatinine clearance is 15­50 mL/min (0.25­0.83 mL/s)

Rivaroxaban 20 mg daily with food 15 mg orally daily with evening meal if creatinine clearance is ≤50 mL/min (0.83 mL/s)

The timing of oral anticoagulant initiation has been in question due to the risk of hemorrhagic conversion of the infarcted area. Guidelines suggest for
patients with a low risk of hemorrhagic conversion, anticoagulation can begin 2 to 14 days after the stroke. However, in patients with a high risk of
hemorrhagic conversion, waiting at least 14 days is recommended.8

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.8 Current guidelines have the following recommendations for BP control after ischemic stroke to prevent future strokes:

Adults with previously treated hypertension who experience a stroke or 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 with hypertension who experience a stroke or TIA, treatment with a thiazide diuretic, angiotensin­converting enzyme (ACE) inhibitor, or
angiotensin II receptor blocker is useful.

Adults not previously treated for hypertension who experience a stroke or TIA and have an average BP of 130/80 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 is recommended.8,34

Cholesterol Management
The statins have been shown to reduce the risk of stroke by approximately 30% in patients with coronary artery disease and elevated plasma
lipids.8 Patients with ischemic stroke without known heart disease but who have LDL cholesterol over 100 mg/dL (2.59 mmol/L) should be given
atorvastatin 80 mg daily to reduce the risk of stroke recurrence.8 Patients with ischemic stroke or TIA who have atherosclerotic cardiovascular disease
(ASCVD) should be given lipid­lowering therapy with a high­intensity statin (and ezetimibe, if necessary) to reach a goal of LDL cholesterol of less than
70 mg/dL (1.81 mmol/L).8 In very high­risk patients (multiple major atherosclerotic cardiovascular events or one major atherosclerotic cardiovascular
event and multiple high­risk conditions) who are taking maximally tolerated statins and ezetimibe with LDL cholesterol ≥70 mg/dL (1.81 mmol/L), a
proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor may be considered.8

Hypertriglyceridemia has recently been recognized as a risk factor for ASCVD but lowering triglycerides with extended­release niacin or fibrates has not
been shown to change cardiovascular outcomes. In contrast, adding icosapent ethyl 2 g twice daily to statin therapy has been shown to reduce major
Downloaded 2022­10­24 2:51 P Your IP is 41.233.255.202
adverse cardiovascular events, including stroke, in patients with fasting triglycerides of 135 to 499 mg/dL (1.53 to 5.64 mmol/L) and LDL cholesterol of
Chapter 39: Stroke, Melody Ryan; Melissa Nestor Page 23 / 35
41 to 100 mg/dL (1.06 to Rights
2.59 mmol/L). 35 Therefore, icosapent ethyl is recommended for these patients with provided they have HbA1c <10% (86
©2022 McGraw Hill. All Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
mmol/mol) and no history of pancreatitis, atrial fibrillation, or severe heart failure.8 When patients have fasting triglycerides of 500 mg/dL (5.65
mmol/L) or more, non­pharmacologic efforts to reduce them should be initiated along with fibrate therapy, if needed.8
70 mg/dL (1.81 mmol/L).8 In very high­risk patients (multiple major atherosclerotic cardiovascular events or one major atherosclerotic cardiovascular
Birzeit University
event and multiple high­risk conditions) who are taking maximally tolerated statins and ezetimibe with LDL cholesterol ≥70 mg/dL (1.81 mmol/L), a
Access Provided by:
proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor may be considered.8

Hypertriglyceridemia has recently been recognized as a risk factor for ASCVD but lowering triglycerides with extended­release niacin or fibrates has not
been shown to change cardiovascular outcomes. In contrast, adding icosapent ethyl 2 g twice daily to statin therapy has been shown to reduce major
adverse cardiovascular events, including stroke, in patients with fasting triglycerides of 135 to 499 mg/dL (1.53 to 5.64 mmol/L) and LDL cholesterol of
41 to 100 mg/dL (1.06 to 2.59 mmol/L).35 Therefore, icosapent ethyl is recommended for these patients with provided they have HbA1c <10% (86
mmol/mol) and no history of pancreatitis, atrial fibrillation, or severe heart failure.8 When patients have fasting triglycerides of 500 mg/dL (5.65
mmol/L) or more, non­pharmacologic efforts to reduce them should be initiated along with fibrate therapy, if needed.8

Hemorrhagic Stroke

Acute Treatment

The stroke council of the AHA/ASA has published guidelines on the management of spontaneous ICH in 2015.6 While the usefulness of pharmacologic
interventions is limited in this stroke type, the management of hypertension and reversal of coagulopathy in anticoagulant­associated ICH should be
considered.

Blood Pressure Management

Hypertension in patients with hemorrhagic stroke increases the risk of hematoma expansion. For patients with ICH presenting with a SBP above 220
mm Hg, aggressive lowering of BP with continuous IV infusion medications is reasonable. Clinical trials have demonstrated that acute lowering of SBP
to a goal of 140 mm Hg is safe and may be effective at improving functional outcomes.6 For patients with SAH due to aneurysm rupture, targeting a SBP
less than 160 mm Hg is reasonable in the time period from symptom onset to aneurysm obliteration.6 Refer to Table 39­3 for a summary of these
recommendations and pharmacologic treatment options.

Anticoagulation Reversal
When ICH occurs in a patient on anticoagulants, the use of reversal agents to correct the medication­induced coagulopathy should be considered. For
patients on warfarin with elevated INR, reversal with vitamin K, typically IV, in combination with a four­factor prothrombin complex concentrate is
recommended. Fresh frozen plasma can be used in place of a prothrombin complex concentrate, if necessary, but is not preferred.6 Idarucizumab may
be considered for reversing the effect of dabigatran specifically.36 Factor Xa inhibitors, such as rivaroxaban and apixaban, may be reversed with
andexanet alfa37 (Table 39­8).

Table 39­8
Selected Anticoagulant Reversal

Drug First­Line Reversal Recommendation Alternate Treatment

Warfarin Vitamin K 10 mg IV ×1 Vitamin K 10 mg IV ×1

­and­ ­and­
4­Factor Prothrombin Complex Concentrate (4PCC) Fresh Frozen Plasma
INR 2 to <4: 25 units/kg, max 2,500 units (FFP) 10­15 mL/kg
INR 4­6: 35 units/kg, max 3,500 units
INR >6: 50 units/kg, max 5,000 units

Dabigatran Idarucizumab 5 gm IV ×1 Hemodialysis

4PCC 50 units/kg

Rivaroxaban Andexanet alfa 400 mg IV Bolus at rate of 30 mg/min, followed by 4 mg/min IV infusion up to 120 4PCC 50 units/kg
≤10 mg minutes

Rivaroxaban If <8 hours since last dose or unknown time andexanet alfa 800 mg IV bolus at rate of 30 mg/min, 4PCC 50 units/kg
>10 mg or unknown followed by 8 mg/min IV infusion up to 120 minutes
dose If ≥8 hours since last dose
Andexanet alfa 400 mg IV Bolus at rate of 30 mg/min, followed by 4 mg/min IV infusion up to 120
Downloaded 2022­10­24 2:51 minutes
P Your IP is 41.233.255.202
Chapter 39: Stroke, Melody Ryan; Melissa Nestor Page 24 / 35
©2022Apixaban
McGraw≤5Hill.
mg All Rights Reserved.
Andexanet Terms
alfa 400 mg IVof Useat• rate
Bolus Privacy
of 30Policy
mg/min,• Notice
followed• by
Accessibility
4 mg/min IV infusion up to 120 4PCC 50 units/kg
minutes
be considered for reversing the effect of dabigatran specifically.36 Factor Xa inhibitors, such as rivaroxaban and apixaban, may be reversed with
andexanet alfa37 (Table 39­8). Birzeit University
Access Provided by:
Table 39­8
Selected Anticoagulant Reversal

Drug First­Line Reversal Recommendation Alternate Treatment

Warfarin Vitamin K 10 mg IV ×1 Vitamin K 10 mg IV ×1

­and­ ­and­
4­Factor Prothrombin Complex Concentrate (4PCC) Fresh Frozen Plasma
INR 2 to <4: 25 units/kg, max 2,500 units (FFP) 10­15 mL/kg
INR 4­6: 35 units/kg, max 3,500 units
INR >6: 50 units/kg, max 5,000 units

Dabigatran Idarucizumab 5 gm IV ×1 Hemodialysis

4PCC 50 units/kg

Rivaroxaban Andexanet alfa 400 mg IV Bolus at rate of 30 mg/min, followed by 4 mg/min IV infusion up to 120 4PCC 50 units/kg
≤10 mg minutes

Rivaroxaban If <8 hours since last dose or unknown time andexanet alfa 800 mg IV bolus at rate of 30 mg/min, 4PCC 50 units/kg
>10 mg or unknown followed by 8 mg/min IV infusion up to 120 minutes
dose If ≥8 hours since last dose
Andexanet alfa 400 mg IV Bolus at rate of 30 mg/min, followed by 4 mg/min IV infusion up to 120
minutes

Apixaban ≤5 mg Andexanet alfa 400 mg IV Bolus at rate of 30 mg/min, followed by 4 mg/min IV infusion up to 120 4PCC 50 units/kg
minutes

Apixaban >5 mg or If <8 hours since last dose or unknown time 4PCC 50 units/kg
unknown dose Andexanet alfa 800 mg IV bolus at rate of 30 mg/min, followed by 8 mg/min IV infusion up to 120
minutes
If ≥8 hours since last dose
Andexanet alfa 400 mg IV Bolus at rate of 30 mg/min, followed by 4 mg/min IV infusion up to 120
minutes

Edoxaban Andexanet alfa not studied 4PCC 50 units/kg

FFP, fresh frozen plasma; IV, intravenous; 4PCC, 4­factor prothrombin complex concentrate; INR, international normalized ratio.

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 (a) extension of the original lesion—ischemic or hemorrhagic—in the brain, (b) development
of cerebral edema and elevated intracranial pressure, (c) hypertensive emergency, (d) infection (urinary and respiratory most common), (e) venous
thromboembolism (deep vein thrombosis 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 39­9. The plan should be customized for individual
patients based on the etiology of the stroke, their comorbidities, and ongoing disease processes.

TABLE 39­9
Monitoring Stroke Therapy in Hospitalized Patients
Downloaded 2022­10­24 2:51 P Your IP is 41.233.255.202
Chapter 39: Stroke, Melody Ryan; Melissa Nestor Page 25 / 35
©2022DMcGraw
rug
Hill. All Rights Reserved. Terms of UseMonitoring
Adverse Effect
• Privacy Policy • Notice • Accessibility
Parameters Comments

Alteplase and tenecteplase Bleeding Neurologic examination, Every 15 minutes × 1 hour; every 30 minutes × 6 hours; every 1
with brain injury), and (g) recurrent stroke.
Birzeit University
The approach to monitoring drug therapy in the hospitalized stroke patient is summarized in Table 39­9. The plan should be customized for individual
Access Provided by:
patients based on the etiology of the stroke, their comorbidities, and ongoing disease processes.

TABLE 39­9
Monitoring Stroke Therapy in Hospitalized Patients

Drug Adverse Effect Monitoring Parameters Comments

Alteplase and tenecteplase Bleeding Neurologic examination, Every 15 minutes × 1 hour; every 30 minutes × 6 hours; every 1
blood pressure hour × 17 hours; every shift after

Aspirin Bleeding Daily

Clopidogrel Bleeding Daily

Extended­release Headache, bleeding Daily

dipyridamole plus aspirin

Ticagrelor Bleeding, Heart rate, respiratory rate Bleeding daily, heart rate and respiratory rate as clinically
bradycardia, indicated
dyspnea

Direct­acting oral Bleeding Daily

anticoagulants

Warfarin Bleeding PT/INR, hemoglobin, Daily

hematocrit

INR, international normalized ratio; PT, prothrombin time.

For survivors of noncardioembolic strokes, approximately 3% to 4% per year will experience another stroke. One­third to one­half of these strokes
occur while patients are on antiplatelet therapy to prevent stroke.38 None of these agents reduces stroke risk to zero; some of the most important
causes of breakthrough strokes are nonadherence, inappropriate dosing, reduced absorption, increased metabolism, drug­drug interactions, and
genetic polymorphisms.38 The healthcare practitioner is in a position to impact several of these factors. Nonadherence can have a root cause in a lack
of understanding of therapy, adverse effects of the therapy, or the number of medications on discharge, among other factors.

CONCLUSION
Treatment of stroke requires a team approach to provide an accurate diagnosis to guide treatment and select therapies proven to improve outcomes.
Careful patient selection for pharmacologic and nonpharmacologic therapies is paramount. Monitoring treatment helps assure goals of therapy are
met.

ABBREVIATIONS

ACE angiotensin­converting enzyme

ADP adenosine diphosphate

AHA American Heart Association

aPTT activated partial thromboplastin time

ATP adenosine triphosphate

Downloaded 2022­10­24 2:51 P Your IP is 41.233.255.202
Chapter 39: Stroke, Melody Ryan; Melissa Nestor Page 26 / 35
AVM arteriovenous malformation
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility

ASA American Stroke Association

 Birzeit University
AHA American Heart Association
Access Provided by:

aPTT activated partial thromboplastin time

ATP adenosine triphosphate

AVM arteriovenous malformation

ASA American Stroke Association

ASCVD atherosclerotic cardiovascular disease

BP blood pressure

cAMP cyclic adenosine monophosphate

CD carotid Doppler

cGMP cyclic guanosine monophosphate

COX cyclooxygenase

CNS central nervous system

CT scan computed tomography

CTA computed tomography angiography

CYP2C19 cytochrome P450 isoenzyme 2C19

DBP diastolic blood pressure

DCI delayed cerebral ischemia

DOAC direct­acting oral anticoagulants

DWI diffusion­weighted imaging

ECG electrocardiogram

EVD external ventricular drainage

FFP fresh frozen plasma

GCS Glasgow Coma Scale

GI gastrointestinal

GLP1 glucagon­like peptide 1

HgA1c hemoglobin A1c

ICA internal carotid artery

ICH intracerebral hemorrhage

INR international normalized ratio

Downloaded 2022­10­24 2:51 P Your IP is 41.233.255.202
Chapter
IPC39: Stroke, Melody Ryan;intermittent
Melissa Nestor
pneumatic compression Page 27 / 35
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
IV intravenous
 Birzeit University
ICA internal carotid artery
Access Provided by:

ICH intracerebral hemorrhage

INR international normalized ratio

IPC intermittent pneumatic compression

IV intravenous

LDL low­density lipoprotein

MCA middle cerebral artery

MI myocardial infarction

MRI magnetic resonance imaging

mRS modified Rankin score

NIHSS National Institutes of Health Stroke Scale

NSAID nonsteroidal anti­inflammatory drug

NVAF nonvalvular atrial fibrillation

PFO patent foramen ovale

P2Y12 purinergic receptor P2Y, G­protein coupled 12

PCC prothrombin complex concentrate

PCSK9 proprotein convertase subtilisin/kexin type 9

PGI2 prostacyclin

PT prothrombin time

SAH subarachnoid hemorrhage

SBP systolic blood pressure

TCD transcranial Doppler

TEE transesophageal echocardiography

TIA transient ischemic attack

TTE transthoracic echocardiography

TXA2 thromboxane A2

REFERENCES

1. Heron M. Deaths: leading causes for 2018. Natl Vital Stat Rep 2021;70(4):1–115.
Downloaded 2022­10­24 2:51 P Your IP is 41.233.255.202
[PubMed:39:
Chapter 34029179] .
Stroke, Melody Ryan; Melissa Nestor Page 28 / 35
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
2. Virani SS, Alonso A, Aparicio HJ, et al. Heart disease and stroke statistics—2021 update. Circulation 2021;143:e254–e743.
10.1161/cir.0000000000000950.
 Birzeit University
Access Provided by:

REFERENCES

1. Heron M. Deaths: leading causes for 2018. Natl Vital Stat Rep 2021;70(4):1–115.
[PubMed: 34029179] .

2. Virani SS, Alonso A, Aparicio HJ, et al. Heart disease and stroke statistics—2021 update. Circulation 2021;143:e254–e743.
10.1161/cir.0000000000000950.

3. Unnithan AKA, Mehta P.Hemorrhagic stroke. Treasure Island, FL: StatPearls Publishing; 2021. https://www.ncbi.nlm.nih.gov/books/NBK559173/.

4. Meschia JF, Bushnell C, Boden­Albala B, et al. Guidelines for the primary prevention of stroke: A statement for health professionals from the
American Heart Association/American Stroke Association. Stroke . 2014;45: 3754–3832. [PubMed: 25355838]

5. Feske SK Ischemic stroke. Am J Med 2021;134:1457–1464. 10.1016/j.amjmed.2021.07.027.

6. Hemphill JC, Greenberg SM, Anderson CS, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: A guideline for
healthcare professionals from the American Heart Association/American Stroke Association. Stroke . 2015;46: 2032–2060. [PubMed: 26022637]

7. Powers WJ, Rabinstein AA, Ackerson T, et al. 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. Stroke 2019;50:e344–e418. 10.1161/str.0000000000000211.

8. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the prevention of stroke in patients with stroke and transient ischemic attack: a
guideline from the American Heart Association/American Stroke Association. Stroke 2021;52:e364–e467. 10.1161/str.0000000000000375.

9. Mojadidi MK, Zaman MO, Elgendy IY, et al. Cryptogenic stroke and patent foramen ovale. J Am Coll Cardiol 2018;71:1035–1043.
10.1016/j.jacc.2017.12.059.

10. Kernan WN, Viera AJ, Billinger SA, et al. Primary care of adult patients after stroke: a scientific statement from the American Heart
Association/American Stroke Association. Stroke 2021;52:e558–e571. 10.1161/str.0000000000000382.

11. Serebruany VL, Malinin AI, Sane DC. Rapid platelet inhibition after a single capsule of Aggrenox: Challenging a conventional full­dose aspirin
antiplatelet advantage? Am J Hematol. 2003;72: 280–281. [PubMed: 12666142]

12. Iqbal AM, Lopez RA, Hai O, Antiplatelet medications. Treasure Island, FL: StatPearls Publishing; 2021.
https://www.ncbi.nlm.nih.gov/books/NBK537062/.

13. Alhazzani A, Venkatachalapathy P, Padhilahouse S, et al. Biomarkers for antiplatelet therapies in acute ischemic stroke: a clinical review. Front
Neurol. 2021;12:667234. 10.3389/fneur.2021.667234.

14. Wiśniewski A. Multifactorial background for a low biological response to antiplatelet agents used in stroke prevention. Medicina . 2021;57:59.
10.3390/medicina57010059.

15. Cai G, Zhou W, Lu Y, et al. Aspirin resistance and other aspirin­related concerns. Neurol Sci. 2016;37: 181–189. [PubMed: 26573589]

16. Del Giovane C, Boncoraglio GB, Bertù L, et al. Antiplatelet drugs for secondary prevention in patients with ischemic stroke or transient ischemic
attack: a systematic review and network meta­analysis. BMC Neurol. 2021;21:319. 10.1186/s12883­021­02341­2.

17. Kubisa MJ, Jezewski MP, Gasecka A, et al. Ticagrelor—toward more efficient platelet inhibition and beyond. Ther Clin Risk Manag. 2018;14: 129–
140. [PubMed: 29398917]

18. Dean L, et al. Clopidogrel therapy and CYP2C19 genotype. Medical Genetics Summaries . Bethesda, MD: National Center for Biotechnology
Information; 2018.

Downloaded 2022­10­24
19. Bristol­Myers 2:51 PPharmaceuticals
Squibb/Sanofi Your IP is 41.233.255.202
Partnership. Plavix Product Information . Bridgewater, NJ: Author; 2021.
Chapter 39: Stroke, Melody Ryan; Melissa Nestor Page 29 / 35
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
20. CAPRIE Steering Committee. A randomized, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet .
1995;348: 1329–1339.
17. Kubisa MJ, Jezewski MP, Gasecka A, et al. Ticagrelor—toward more efficient platelet inhibition and beyond. Ther Clin Risk Manag. 2018;14: 129–
140. [PubMed: 29398917] Birzeit University
Access Provided by:
18. Dean L, et al. Clopidogrel therapy and CYP2C19 genotype. Medical Genetics Summaries . Bethesda, MD: National Center for Biotechnology
Information; 2018.

19. Bristol­Myers Squibb/Sanofi Pharmaceuticals Partnership. Plavix Product Information . Bridgewater, NJ: Author; 2021.

20. CAPRIE Steering Committee. A randomized, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet .
1995;348: 1329–1339.

21. Diener HC, Cunha L, Forbes C, et al. European Stroke Prevention Study 2: Dipyridamole and acetylsalicylic acid in the secondary prevention of
stroke. J Neurol Sci. 1996;143: 1–13. [PubMed: 8981292]

22. Sacco RL, Diener HC, Yusuf S, et al. Aspirin and extended­release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. 2008;359:
1238–1251. [PubMed: 18753638]

23. Johnston SC, Amarenco P, Albers GW, et al. Ticagrelor versus aspirin in acute stroke or transient ischemic attack. New Engl J Med. 2016;375: 35–
43.

24. Amarenco P, Albers GW, Denison H, et al. Efficacy and safety of ticagrelor versus aspirin in acute stroke or transient ischaemic attack of
atherosclerotic origin: A subgroup analysis of SOCRATES, a randomised, double­blind, controlled trial. Lancet Neurol. 2017;16: 301–310. [PubMed:
28238711]

25. Brown DL, Levine DA, Albright K, et al. Benefits and risks of dual versus single antiplatelet therapy for secondary stroke prevention: a systematic
review for the 2021 guideline for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke 2021;52:e468–e479.
10.1161/str.0000000000000377.

26. Johnston SC, Amarenco P, Denison H, et al. Ticagrelor and aspirin or aspirin alone in acute ischemic stroke or TIA. N Engl J Med 2020;383:207–
217. 10.1056/nejmoa1916870.

27. Amarenco P, Denison H, Evans SR, et al. Ticagrelor added to aspirin in acute nonsevere ischemic stroke or transient ischemic attack of
atherosclerotic origin. Stroke . 2020;51:3504–3513. 10.1161/strokeaha.120.032239.

28. Bath PM, Woodhouse LJ, Appleton JP, et al. Triple versus guideline antiplatelet therapy to prevent recurrence after acute ischaemic stroke or
transient ischaemic attack: The TARDIS RCT. Health Technol Assess . 2018;22(48):1–76. [PubMed: 30179153]

29. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients
with atrial fibrillation: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines and the
Heart Rhythm Society in collaboration with the Society of Thoracic Surgeons. Circulation . 2019;140:e125–e151. 10.1161/cir.0000000000000665.

30. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user friendly score (HAS­BLED) to assess 1­year risk of major bleeding in
patients with atrial fibrillation: The Euro Heart Survey. Chest . 2010;138: 1093–1100. [PubMed: 20299623]

31. Hart RG, Benavente O, McBride R, et al. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation. Ann Intern Med. 1999;131:492–
501. 10.7326/0003­4819­131­7­199910050­00003.

32. Martin K, Beyer­Westendorf J, Davidson BL, et al. Use of the direct oral anticoagulants in obese patients: Guidance from the SSC of the ISTH. J
Thromb Haemost. 2016;14: 1308–1313. [PubMed: 27299806]

33. Sebaaly J, Kelley D Direct oral anticoagulants in obesity: an updated literature review. Ann Pharmacother. 2020;54:1144–1158.
10.1177/1060028020923584.

34. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention,
detection, evaluation, and management of high blood pressure in adults: Executive summary. Hypertension . 2018;71: 1269–1324.

35. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380:11–22.
10.1056/nejmoa1812792.
Downloaded 2022­10­24 2:51 P Your IP is 41.233.255.202
Chapter 39: Stroke, Melody Ryan; Melissa Nestor Page 30 / 35
36. Pollack
©2022 CV Jr,Hill.
McGraw Reilly PA, vanReserved.
All Rights Ryn J, et al.Terms
Idarucizumab
of Use • for dabigatran
Privacy Policyreversal:
• Notice Full cohort analysis. N Engl J Med. 2017;377: 431–441. [PubMed:
• Accessibility
28693366]
 Birzeit University
34. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention,
Access Provided by:
detection, evaluation, and management of high blood pressure in adults: Executive summary. Hypertension . 2018;71: 1269–1324.

35. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380:11–22.
10.1056/nejmoa1812792.

36. Pollack CV Jr, Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal: Full cohort analysis. N Engl J Med. 2017;377: 431–441. [PubMed:
28693366]

37. Connolly SJ, Gibson CM, Crowther M, et al. Andexanet alfa for factor Xa inhibitor reversal. N Engl J Med. 2016;375: 2499–500. [PubMed: 28002711]

38. John S, Katzan I. Recurrent stroke while on antiplatelet therapy. Neurol Clin. 2015;33: 475–489. [PubMed: 25907917]

SELF­ASSESSMENT QUESTIONS
1. A cardioembolic stroke is a type of ______________ stroke.

A. Hemorrhagic

B. Ischemic

C. Lacunar

D. Cerebellar

2. Which of the following pairs correctly matches the type of hemorrhagic stroke to one of its potential causes?

A. Intracerebral hemorrhage: the rupture of an intracerebral aneurysm

B. Intracerebral hemorrhage: trauma

C. Subarachnoid hemorrhage: the rupture of an arteriovenous malformation

D. Subarachnoid hemorrhage: uncontrolled hypertension

3. RT is a 77­year­old man who presents to the emergency department with symptoms of an ischemic stroke. Past medical history includes
hypertension, hypothyroidism, benign prostatic hypertrophy, and hypercholesterolemia. What are RT’s stroke risk factors?

A. Age, hypertension, and hypercholesterolemia

B. Age, sex, hypertension, hypothyroidism, and hypercholesterolemia

C. Age, sex, hypertension, and hypercholesterolemia

D. Sex, hypothyroidism, benign prostatic hypertrophy, and hypercholesterolemia

E. Sex, hypertension, and hypercholesterolemia

4. Which of the following is not a symptom of an acute stroke?

A. Inability to speak

B. Loss of vision

C. Weakness on one side of the body

D. Whole body numbness

5. Who is the best candidate for carotid stenting to reduce recurrent stroke?

A. A 65­year­old
Downloaded female
2022­10­24 withP50%
2:51 stenosis
Your of the ipsilateral internal carotid artery
IP is 41.233.255.202
Chapter 39: Stroke, Melody Ryan; Melissa Nestor Page 31 / 35
B. AMcGraw
©2022 65­year­old
Hill. male with 75%
All Rights stenosisTerms
Reserved. of the ipsilateral internal
of Use • Privacy carotid
Policy artery • Accessibility
• Notice

C. A 75­year­old male with 50% stenosis of the ipsilateral internal carotid artery
 C. Weakness on one side of the body
Birzeit University
D. Whole body numbness Access Provided by:

5. Who is the best candidate for carotid stenting to reduce recurrent stroke?

A. A 65­year­old female with 50% stenosis of the ipsilateral internal carotid artery

B. A 65­year­old male with 75% stenosis of the ipsilateral internal carotid artery

C. A 75­year­old male with 50% stenosis of the ipsilateral internal carotid artery

D. A 75­year­old female with 75% stenosis of the ipsilateral internal carotid artery

6. BN is an 84­year­old male who presents to the emergency department with acute ischemic stroke symptoms. Symptoms began 2 hours ago. Current
blood pressure is 176/98 mm Hg and glucose is 110 mg/dL (6.1 mmol/L). A computed tomography (CT) scan of the head that shows no bleeding.
The patient is currently taking aspirin 81 mg daily and lisinopril 10 mg daily. He has no medication allergies. Is BN a candidate for alteplase?

A. Yes.

B. No, his symptoms began too long ago.

C. No, he is too old.

D. No, he is taking aspirin.

7. KC is a 65­year­old woman who presents to the emergency department with acute ischemic stroke symptoms. Symptoms began 6 hours ago.
Current blood pressure is 170/96 mm HG and her glucose is 104 mg/dL (5.8 mmol/L). A computed tomography (CT) scan of the head that shows no
bleeding. The patient is currently taking hydrochlorothiazide 25 mg daily and is allergic to aspirin (oral facial edema). Is KC a candidate for
alteplase?

A. Yes.

B. No, her symptoms began too long ago.

C. No, she is too old.

D. No, she is taking hydrochlorothiazide.

8. ST is a 68­year­old woman who presented with an ischemic stroke 2 days ago. The patient received alteplase and the neurological deficits
improved. Prior to the stroke, the patient was taking no medications. The patient is allergic to aspirin (hives and shortness of breath). Which of the
following agents should ST receive to prevent recurrent strokes?

A. Aspirin

B. Clopidogrel

C. Clopidogrel plus aspirin

D. Extended­release dipyridamole plus aspirin

9. FR is a 58­year­old man who has had atrial fibrillation for 5 years. The patient was maintained on aspirin 325 mg daily. Four days ago, the patient
sustained an ischemic stroke. What is the best choice of therapy for FR to prevent recurrent stroke?

A. Aspirin

B. Clopidogrel

C. Extended­release dipyridamole plus aspirin

D. Rivaroxaban

10. JC is a 79­year­old 150 kg man who recently sustained an ischemic stroke. During the workup, the patient was found to have atrial fibrillation. Blood
pressure is 145/90 mm Hg. Serum creatinine is 4.5 mg/dL (398 µmol/L) (creatinine clearance 28 mL/min [0.47 mL/s]) and BMI is 50 kg/m2. Which of
Downloaded 2022­10­24 2:51 P Your IP is 41.233.255.202
the following
Chapter oralMelody
39: Stroke, anticoagulants is mostNestor
Ryan; Melissa appropriate for JC? Page 32 / 35
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
A. Apixaban 5 mg daily
 C. Extended­release dipyridamole plus aspirin Birzeit University
Access Provided by:
D. Rivaroxaban

10. JC is a 79­year­old 150 kg man who recently sustained an ischemic stroke. During the workup, the patient was found to have atrial fibrillation. Blood
pressure is 145/90 mm Hg. Serum creatinine is 4.5 mg/dL (398 µmol/L) (creatinine clearance 28 mL/min [0.47 mL/s]) and BMI is 50 kg/m2. Which of
the following oral anticoagulants is most appropriate for JC?

A. Apixaban 5 mg daily

B. Edoxaban 30 mg daily

C. Dabigatran 150 mg twice daily

D. Warfarin adjusted to a target INR of 2 to 3

11. What is the HAS­BLED score for JC from question 10?

A. 1

B. 2

C. 3

D. 4

12. RG is a 74­year­old man who is being discharged from the hospital after a mild stroke. Blood pressure has stabilized at 156/98 mm Hg. Low­density
lipoprotein cholesterol is 110 mg/dL (2.84 mmol/L). On which of the following regimens should RG be placed?

A. Atorvastatin 40 mg daily

B. Hydrochlorothiazide 25 mg daily plus rosuvastatin 20 mg daily

C. Lisinopril 5 mg daily

D. Lovastatin 40 mg daily plus losartan 50 mg daily

13. Which of the following is an appropriate monitoring parameter for a patient given alteplase?

A. Bleeding

B. Blue discoloration of the skin

C. Headache

D. Tongue swelling

14. BC is a 58­year­old man with atrial fibrillation who sustained an ischemic stroke and was placed on warfarin. Which of the following is an
appropriate monitoring plan for BC?

A. Check blood glucose daily

B. Check blood pressure three times daily

C. Monitor INR for a target of 2 to 3

D. Monitor tyramine­containing food consumption

15. MP is a 66­year­old woman who sustained an ischemic stroke and was discharged on clopidogrel 75 mg daily plus aspirin 81 mg daily for 21 days.
Which of the following will help decrease the patient’s chance of recurrent stroke?

A. Follow­up regarding adherence

B. Frequently monitoring her blood pressure

Downloaded 2022­10­24 2:51 P Your IP is 41.233.255.202
Chapter 39: Stroke,
C. Frequently Melody Ryan;
monitoring Melissa Nestor
her weight
Page 33 / 35
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
D. Screening for depression
15. MP is a 66­year­old woman who sustained an ischemic stroke and was discharged on clopidogrel 75 mg daily plus aspirin 81 mg daily for 21
Birzeit days.
University
Which of the following will help decrease the patient’s chance of recurrent stroke? Access Provided by:

A. Follow­up regarding adherence

B. Frequently monitoring her blood pressure

C. Frequently monitoring her weight

D. Screening for depression

SELF­ASSESSMENT QUESTION­ANSWERS
1. B . The two major types of stroke are ischemic and hemorrhagic. Ischemic strokes are often the result of large artery atherosclerosis, small artery
disease, or cardioembolism. These three subtypes are the most common etiologies of ischemic strokes. See “Etiology” section for further description.

2. C . Subarachnoid hemorrhage occurs when blood enters the subarachnoid space, which can occur due to trauma, rupture of an intracerebral
aneurysm, or rupture of an arteriovenous malformation. Intracerebral hemorrhage, however, occurs when bleeding occurs in the brain parenchyma
itself, with the formation of a hematoma within the brain. Uncontrolled hypertension is the most common causative factor for intracerebral
hemorrhage, but antithrombotic therapy, cerebral amyloid angiopathy, and some drugs of abuse are also associated with intracerebral hemorrhage.
See “Etiology” section for further description.

3. C . The nonmodifiable stroke risk factors are age, race, sex, low birth weight, and genetic factors. The most common modifiable, well­documented
risk factors for ischemic stroke include hypertension, cigarette smoking, diabetes, atrial fibrillation, and dyslipidemia. See “Risk Factors” section for a
comprehensive review.

4. D . Symptoms of acute stroke include weakness on one side of the body, inability to speak, loss of vision, vertigo and/or falling and occasionally
headache. Stroke symptoms tend to involve only one side of the body. See the Clinical Presentation box for a review of stroke presentation.

5. B . In patients younger than 70 years with 70% to 99% stenosis of an ipsilateral internal carotid artery, carotid stenting can be performed. See
“Nonpharmacologic Therapy” section for more details.

6. A . This patient is within the 4.5­hour window for alteplase administration, his blood pressure is <180/110 mm Hg, and he has no intracranial
bleeding. Patients can be maintained on aspirin and receive alteplase. Please see and Table 39­2 for blood pressure management and criteria for
alteplase use in the setting of acute stroke.

7. B . This patient is not within the 4.5­hour window for alteplase administration. Please see Table 39­4 for criteria for alteplase use in the setting of
acute stroke.

8. B . This patient is allergic to aspirin; thus, it should not be a component of her therapy. Please see “Antiplatelet Agents” section for further discussion
of the antiplatelet agents.

9. D . Oral anticoagulation is the treatment of choice for the prevention of stroke in patients with atrial fibrillation. Choice of agent may include
warfarin, dabigatran, rivaroxaban, edoxaban, and apixaban. Please see “Oral Anticoagulant” section for more details on choosing between these
agents.

10. D . The direct­acting oral anticoagulant doses need to be adjusted for patients with renal dysfunction. There is limited information on the use of
these agents in patients with a body mass index over 40 kg/m2. Therefore, warfarin would be the better choice for this patient. See “Oral
Anticoagulant” section for more details of dosing these agents in decreased renal functioning.

11. B . This patient would receive points for a history of stroke and his age (>65 years). See Table 39­7 for HAS­BLED scoring.

12. B . This patient will require blood pressure lowering because his blood pressure is >140/90 mm Hg. He will also require high­intensity statin therapy
because he is less than 75 years old. See “Blood Pressure Management” and “Statins” sections for additional review of this topic.

13. A . It is appropriate to monitor bleeding in a patient given alteplase. See Table 39­9 for additional monitoring parameters for hospitalized patients
with ischemic stroke.

14. C . Target INR for patients with atrial fibrillation who are given warfarin is 2.5. See Table 39­2.

Downloaded
15. A . Some of2022­10­24 2:51 P Your
the most important IP of
causes is breakthrough
41.233.255.202
strokes are nonadherence, inappropriate dosing, reduced absorption, increased
Chapter 39: Stroke, Melody Ryan; Melissa Nestor Page 34 / 35
metabolism, drug­drug interactions, and genetic polymorphisms. Monitoring blood pressure, weight, or mood are unlikely to decrease future strokes.
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
See “Evaluation of Therapeutic Outcomes” section.
 Birzeit patients
13. A . It is appropriate to monitor bleeding in a patient given alteplase. See Table 39­9 for additional monitoring parameters for hospitalized University
Access Provided by:
with ischemic stroke.

14. C . Target INR for patients with atrial fibrillation who are given warfarin is 2.5. See Table 39­2.

15. A . Some of the most important causes of breakthrough strokes are nonadherence, inappropriate dosing, reduced absorption, increased
metabolism, drug­drug interactions, and genetic polymorphisms. Monitoring blood pressure, weight, or mood are unlikely to decrease future strokes.
See “Evaluation of Therapeutic Outcomes” section.

Downloaded 2022­10­24 2:51 P Your IP is 41.233.255.202

Chapter 39: Stroke, Melody Ryan; Melissa Nestor Page 35 / 35
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility