Acute Ischemic Stroke

Acute Ischemic Stroke

By Steven H. Nakajima, Pharm.D., BCCCP; and Katleen Wyatt Chester, Pharm.D., BCCCP, BCGP

Reviewed by Dennis Parker, Jr., Pharm.D.; Abigail M. Yancey, Pharm.D., FCCP, BCPS; and Marcus Patrick, Pharm.D., BCPS

LEARNING OBJECTIVES

1. Design a patient-specific pharmacotherapeutic regimen to treat adverse events associated with intravenous alteplase, including hemorrhage and angioedema.

2. Distinguish key differences between the most recent guidelines for early management of acute ischemic stroke and the previous guidelines.

3. Assess a patient's candidacy for intravenous fibrinolytic therapy on the basis of updated inclusion and exclusion recommendations.

4. Evaluate the role of thrombolysis and thrombectomy with respect to eligibility criteria, efficacy, complications, and post-intervention considerations.

5. Devise an evidence-based, patient-specific antiplatelet plan for early secondary prevention after minor ischemic stroke or high-risk transient ischemic attack.

6. Justify the pharmacist's role as an integral part of the stroke response team for acute ischemic stroke.

ABBREVIATIONS IN THIS CHAPTER

AIS

Acute ischemic stroke

DAPT

Dual antiplatelet therapy

DTN

Door-to-needle time

EVT

Endovascular therapy

ICH

Intracranial hemorrhage

LVO

Large vessel occlusion

MCA

Middle cerebral artery

mRS

Modified Rankin Scale

NIHSS

National Institutes of Health Stroke Scale

NINDS

National Institute of Neurological Disorders and Stroke

TIA

Transient ischemic attack

TICI

Thrombolysis in Cerebral

Infarction

Table of other common abbreviations.

PSAP 2020 Book 1 ? Critical and Urgent Care

INTRODUCTION

Stroke is the leading cause of serious long-term disability and the fifth leading cause of death for Americans. On average, someone in the United States has a stroke every 40 seconds, resulting in about 795,000 strokes per year. Ischemic strokes account for 87% of cases, whereas 10% are intracerebral hemorrhage and 3% are subarachnoid hemorrhage. The burden of stroke in the United States resulted in direct and indirect costs that averaged $33.9 billion annually in 2013 (Benjamin 2017).

Acute ischemic stroke (AIS) can affect the anterior circulation, the posterior circulation, or both. The internal carotid arteries supply oxygenated blood to the anterior circulation of the brain (i.e., middle cerebral arteries [MCAs] and anterior cerebral arteries), and the posterior circulation is supplied by the vertebral arteries that merge into the basilar artery, which feeds into the posterior cerebral and posterior communicating arteries. These anterior and posterior arteries that make up the circle of Willis (Figure 1) are called proximal arteries, given their proximity to the circle itself. Anterior circulation strokes involving the internal carotid artery and MCA are more common than posterior infarcts.

The vascular territory and the volume of ischemic brain tissue determine the type and severity of deficits. Patients with anterior strokes may present with focal deficits such as aphasia, neglect, hemiplegia, hemisensory loss, or visual field deficits. Patients with posterior strokes usually have a broad range of symptoms, including gait disturbances, unilateral or bilateral ataxia, visual field disturbances, optic ataxia, nystagmus, and even unresponsiveness and

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Acute Ischemic Stroke

respiratory arrest in the case of a complete, proximal basilar artery occlusion. Proximal arterial occlusions tend to result in larger volumes of ischemic brain tissue (and therefore a broader array and increased severity of stroke symptoms), whereas occlusions more distally or in small arteries typically produce an isolated deficit of lower severity.

Acute ischemic stroke can be categorized into five subtypes depending on the cause, as described by the TOAST investigators (Adams 1993). These subtypes are large-artery atherosclerosis, cardioembolic, small vessel occlusion (lacunar), stroke of other determined cause, and stroke

Int. carotid

Ant. communicating Ant. cerebral

A.M. Arterial circle

Mid. cerebral A.L.

P.M.

Post communicating

Basilar

BASELINE KNOWLEDGE STATEMENTS

Readers of this chapter are presumed to be familiar with the following:

? General knowledge of the pathophysiology of AIS ? Understanding of the pharmacology of aspirin,

fibrinolytics, and P2Y12 receptor inhibitors

? Knowledge of pharmacotherapy for secondary prevention of stroke

Table of common laboratory reference values

ADDITIONAL READINGS

The following free resources have additional background information on this topic:

? 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.

? Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scientific Rationale for the Inclusion and Exclusion Criteria for Intravenous Alteplase in Acute Ischemic Stroke: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2016;47:581-641.

? Yaghi S, Willey JZ, Cucchiara B, et al. Treatment and Outcome of Hemorrhagic Transformation After Intravenous Alteplase in Acute Ischemic Stroke: A Scientific Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2017;48:e343-e61.

? Frontera JA, Lewin JJ, Rabinstein AA, et al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care 2016;24:6-46.

Pontine

P.L.

Internal auditory

Vertebral

Anterior Spinal

Posterior inferior cerebellar

Figure 1. Arterial circulation at the base of the brain, "the circle of Willis." A.L. = anterolateral ganglionic branches; A.M. = anteromedial ganglionic branches; Ant. = anterior; Int. = internal; arterial circle = "the circle of Willis"; P.L. = posterolateral ganglionic branches; P.M. = posteromedial ganglionic branches; Post = posterior. Image reprinted from: Gray H. Anatomy of the Human Body. Philadelphia: Lea & Febiger, 1918; Figure 519.

of undetermined cause. Table 1 outlines the definitions, incidence, and survival rates from a population-based epidemiology study (Kolominsky-Rabas 2001). The TOAST categorization is useful to both clinicians and researchers. For clinicians, this categorization helps classify the cause in order to formulate a therapeutic plan to mitigate risk factors and potentially prevent future stroke events. For researchers, this classification defines different stroke subtypes to more clearly identify risk factors and to evaluate the safety and efficacy of potential new therapies.

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Acute Ischemic Stroke

Table 1. TOAST Classifications

TOAST Classification

Incidence Definition

Support for Diagnosis

2-Yr

2-Yr

Survival Recurrence

Undetermined causes

31% a. Two or more causes

Diagnosis of exclusion

identified,

b. Negative evaluation, OR

c. Incomplete evaluation

61%

14%

Cardioembolic

29% Arterial embolism of cardiac origin

High-risk cardiac sources: Mechanical

55%

22%

prosthetic valve, atrial fibrillation,

left atrial appendage thrombus, left

ventricular thrombus, and dilated

cardiomyopathy

Small-artery "lacunar"

21% No recognizable lesion on Lacunar syndrome (e.g., pure motor

CT or MRI or a subcortical hemiparesis, pure sensory stroke,

or brain stem lesion

sensorimotor stroke, or ataxic

< 1.5 cm diameter

hemiparesis)

History of diabetes mellitus and/or

hypertension

85%

11%

Large-artery

15% > 50% stenosis of a large History of intermittent claudication,

58%

10%

atherosclerosis

artery with a > 1.5-cm

carotid bruit, TIAs, or diminished pulses

atherosclerotic lesion, no

cardioembolic source

Stroke of other cause

5%

Identified source of stroke Examples include hypercoagulable

Variable Variable

different fromearlier

states, vasculopathies, hematologic

classifications

disorders

CT = computed tomography; TIA = transient ischemic attack.

Information from: Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993;24:35-41; Kolominsky-Rabas PL, Weber M, Gefeller O, et al. Epidemiology of ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and longterm survival in ischemic stroke subtypes: a population-based study. Stroke 2001;32:2735-40; Krishnamurthi RV, Barker-Collo S, Parag V, et al. Stroke incidence by major pathological type and ischemic subtypes in the Auckland Regional Community Stroke Studies: changes between 2002 and 2011. Stroke 2018;49:3-10.

THERAPEUTIC GOALS

Therapeutic goals for ischemic stroke can be categorized as acute versus chronic. Although chronic management goals focus towards secondary prevention of ischemic events, initial acute treatment goals focus on reducing infarct size and stroke severity to ultimately return a patient to baseline functional status. Acute treatment aims for timely restoration of blood flow to ischemic areas to limit the volume of unsalvageable brain tissue, known as the ischemic core. Acute treatment also focuses on preserving the penumbra, which is an area of salvageable, ischemic neurons surrounding the core infarct that can be recovered by timely reperfusion.

Outcomes from landmark AIS trials focus on eliminating or reducing the severity of stroke-related deficits and improving functional status at 90 days. The 2019 guidelines prefer the National Institutes of Health Stroke Scale score (NIHSS), a validated scoring tool for measuring stroke deficits (Brott 1989, Powers 2019). The NIHSS generates a value of 0?42, with 0 representing the absence of ischemic stroke deficits

and 42 representing the highest severity of deficits (Table 2). The NIHSS is rapidly performed and is valuable for its ability to determine stroke severity while serving as a tool for measuring changes in clinical status (Table 3).

Varying definitions of stroke severity have been defined in the literature, with severe strokes usually identified as an NIHSS score of more than 15 to 20 points. Although clinicians and researchers also use varying thresholds for defining clinically relevant changes in the NIHSS, differences in NIHSS scores of 1, 4, or 8 are used most in thrombolytic trials (Kwah 2014; Schlegel 2003). Besides stroke severity, the NIHSS score also predicts long-term outcomes. Despite some limitations, the NIHSS is the most widely used rating scale for identifying candidates for reperfusion therapies such as thrombolysis and thrombectomy.

The modified Rankin Scale (mRS) is the gold standard tool for categorizing functional status in patients with stroke (van Swieten 1988). The mRS ranges from 0 to 6, with 0 representing the absence of disability and 6 representing death

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Acute Ischemic Stroke

Table 2. NIHSS Score

Category

1a. LOC

1b. LOC questions 1c. LOC commands 2. Gaze 3. Visual fields

Score/Description

0 = Alert 1 = Drowsy 2 = Stuporous 3 = Coma

0 = Answers both correctly 1 = Answers one correctly 2 = Incorrect

0 = Obeys both correctly 1 = Obeys one correctly 2 = Incorrect

0 = Normal 1 = Partial gaze palsy 2 = Forced deviation

0 = No visual loss 1 = Partial hemianopia 2 = Complete hemianopia 3 = Bilateral hemianopia

4. Facial paresis

0 = Normal 1 = Minor 2 = Partial 3 = Complete

5a. Motor arm ? Left 5b. Motor arm ? Right

0 = No drift 1 = Drift 2 = Cannot resist gravity 3 = No effort against gravity 4 = No movement X = Untestable

Category

6a. Motor leg ? Left 6b. Motor leg ? Right

Score/Description

0 = No drift 1 = Drift 2 = Cannot resist gravity 3 = No effort against gravity 4 = No movement X = Untestable

7. Limb ataxia 8. Sensory 9. Language

10. Dysarthria

11. Extinction/ inattention

0 = No ataxia 1 = Present in one limb 2 = Present in two limbs

0 = Normal 1 = Partial loss 2 = Severe loss

0 = No aphasia 1 = Mild to moderate aphasia 2 = Severe aphasia 3 = Mute X = Untestable

0 = Normal articulation 1 = Mild to moderate slurring of words 2 = Near to unintelligible or worse X = Intubated or other physical barrier

0 = No neglect 1 = Partial neglect 2 = Complete neglect

LOC = level of consciousness; NIHSS = National Institutes of Health Stroke Scale.

Information from: Richardson J, Murray, D, House CK, et al. Successful implementation of the National Institutes of Health Stroke Scale on a stroke/neurovascular unit. J Neurosci Nurs 2006;38:309-15.

(Table 4). Disability status, as measured by the mRS, is generally determined at discharge and again at 90 days because most patients who achieve functional recovery do so within this timeframe (Duncan 2000). The clinical significance of a 1-point change in mRS depends on the baseline value of the mRS. For example, a change from 0 to 1 indicates a low impact on daily activities, whereas a change in mRS from 3 to 4 indicates that the patient can no longer ambulate without assistance.

INTRAVENOUS FIBRINOLYTICS

Alteplase

Alteplase is a recombinant tissue-type plasminogen activator (rtPA) that exerts its therapeutic effect through initiating fibrinolysis (also referred to as thrombolysis). Specifically, rtPA cleaves plasminogen at the Arg561-Val562 peptide bond, forming plasmin. Plasmin is an endogenous

protease enzyme that cleaves the cross-links between fibrin molecules, thus disrupting the mesh-like structure of a fibrin-based blood clot. Alteplase's FDA-approved labeling includes treatment of AIS at a dose of 0.9 mg/kg intravenously once with a maximum total dose of 90 mg. Ten percent of the dose (0.09 mg/kg) is given as a bolus over 1 minute, with the remaining 90% (0.81 mg/kg) infused over 1 hour. The biggest concern with administering intravenous alteplase for AIS is the risk of symptomatic intracranial hemorrhage (ICH), which occurs in 2 to 7 percent of patients (Frontera 2016). ICH is usually the result of hemorrhagic conversion within the infarcted territory. Providing broad clinical guidance on alteplase use is a delicate balance. Liberal interpretation of relative contraindications may increase the risk of ICH, whereas conservative approaches may limit how many patients benefit from this therapy.

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Acute Ischemic Stroke

Table 3. NIHSS Definitions of Severity and Relationship with Hospital Discharge Disposition

NIHSS Score

0 or 1 1?4 5?14

15?25 > 25

Stroke Severity

Normal Mild Mild to moderately severe Severe Very severe

Discharge Disposition

Discharge home

Acute inpatient rehabilitation

Long-term acute care

NIHSS = National Institutes of Health Stroke Scale.

Information from: Schlegel D, Kolb SJ, Luciano JM, et al. Utility of the NIH Stroke Scale as a predictor of hospital disposition. Stroke 2003;34:134-7.

Acute Blood Pressure Management About 70% of patients presenting with stroke have a blood pressure of 170/110 mm Hg or greater (Britton 1986). Severe hypertension must be managed acutely if a patient is otherwise eligible to receive intravenous alteplase. The goal of acute management of blood pressure is to achieve a blood pressure less than 185/110 mm Hg to initiate alteplase and maintain a blood pressure of less than 180/105 mm Hg while alteplase is being infused and for the 24 hours after administration (Powers 2019). If the patient is not a candidate for intravenous fibrinolysis or mechanical thrombectomy, permissive hypertension, up to 220/120 mm Hg, is recommended to maintain cerebral perfusion to the penumbra. In these patients with no other indication for urgent hypertension treatment, the benefit of treatment of hypertension in the first 48 to 72 hours is uncertain (Powers 2019). The guidelines

state it may be reasonable to lower the blood pressure by fifteen percent in the first 24 hours after onset of strokes in this select population. Ideal agents for acute control of blood pressure have a rapid onset, are available for intravenous administration, have a short half-life, and have a predictable blood pressure lowering to dose response. There is no evidence that one antihypertensive is preferred to another in the setting of AIS. Common blood pressure?lowering agents are labetalol, nicardipine, clevidipine, and hydralazine (Table 5).

The optimal target for blood pressure during and after intravenous alteplase was recently evaluated. Published in February 2019, the ENCHANTED trial randomized 2196 patients with hypertension receiving alteplase to a systolic blood pressure (SBP) goal of 130?140 mm Hg within 1 hour (intensive blood pressure?lowering cohort) or to a goal SBP of less than 180 mm Hg (guideline-based blood pressure cohort) (Anderson 2019). Functional outcome (shift in mRS) at 90 days was the primary efficacy end point, and the primary safety outcome was any ICH. The incidence of ICH was lower in the intensive-lowering group (14.8% vs. 18.7%; OR 0.75; 95% CI, 0.60?0.94; p=0.0137); however, the primary outcome of functional status at 90 days did not differ between the groups (unadjusted OR 1.01; 95% CI, 0.87?1.17; p=0.8702). Despite reduced rates of ICH, no change in functional outcome was shown. These findings call into question the benefit of intensive blood pressure lowering, and subsequent editorials from stroke experts, including the authors of this study, advise caution in interpreting the lower rates of ICH as a positive indicator of this therapy. The positive outcomes associated with the lower rate of ICH could have been negated by the negative impact on cerebral perfusion with intensive blood pressure lowering, possibly leading to the net neutral effect on functional outcomes at 90 days. According to this study alone, intensive blood pressure lowering postalteplase may not be necessary or beneficial.

Table 4. Modified Rankin Scale

Independent Dependent

Value Description

0 No symptoms 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily

needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead

Information from: van Swieten JC, Koudstaal PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988;19:604-7.

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Acute Ischemic Stroke

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