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
Table 5. Options for Antihypertensive Agents in Acute Stroke
Medication Dose
Onset
Duration
Labetalol
10?20 mg slow IV push q5min, doubling dose until effect. May follow with an IV infusion at 2 mg/min. Titrate to max of 8 mg/min.
Within 5 min
16?18 hr (dose dependent)
Nicardipine 5 mg/hr IV continuous, titrate by 2.5 mg/hr q5?15min. Max 15 mg/hr
Within 5 min; 50% of max effect at 50% decrease in effect by 45 min with continuous infusion 30 min after discontinuation
Clevidipine 1?2 mg/hr IV continuous, titrate by doubling dose q2?5min. Max 21 mg/hr
2?4 min
5?15 min
Hydralazine 10?20 mg IV push q4?6hr, max single dose 40 mg 10?80 min
Up to 12 hr
Enalaprilat 1.25 mg slow IV push over 5 min q6hr
Within 15 min, peak effect 1?4 hr 6 hr
IV = intravenous(ly); q = every.
Information from: 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.
Management of Adverse Events The incidence of ICH after alteplase administration for AIS depends on several factors, including age, weight, history of hypertension, current antiplatelet therapy, baseline NIHSS score, blood glucose, SBP, and time since symptom onset (Mazya 2012). This complication can be devastating, with rates of hematoma expansion of up to 40% and 3-month mortality as high as 60%. "Reversal" of intravenous thrombolytics is usually indicated for symptomatic ICH with decline in neurologic function within the first 24 hours after administration. This may seem counterintuitive, given that the plasma half-life of alteplase is only 4 minutes; however, the terminal half-life is 72?100 minutes, and studies have noted a decrease in fibrinogen concentrations at 24 hours after administration. Treatment of thrombolytic-related ICH has great uncertainty, and guidance is limited to theoretical mechanisms, a heterogeneous mix of case series, and a few small, underpowered retrospective studies. Recommendations for managing ICH after alteplase in patients with AIS are available from the 2019 American Heart Association/American Stroke Association (AHA/ASA) guidelines for the early treatment of patients with AIS (Powers 2019) and the Neurocritical Care Society (NCS) guideline for reversal of antithrombotics in ICH (Frontera 2016). A summary of these recommendations is listed in Table 6.
The recommendation for cryoprecipitate administration after alteplase-related ICH is based on a single, multicenter, retrospective study. This trial evaluated risk factors for patients with symptomatic ICH after receiving alteplase for AIS (Yaghi 2015). In this study, a fibrinogen concentration of less than 150 mg/dL was the only statistically significant predictor of hematoma expansion. Because cryoprecipitate contains fibrinogen 200 mg/unit (and can increase fibrinogen
concentrations by about 70 mg/dL after 10 units given to a patient weighing 70 kg), administration of this blood product to target a fibrinogen concentration of greater than 150 mg/dL is theorized to decrease the risk of further expansion. This theory, however, has never been prospectively evaluated, and retrospective studies have been underpowered to detect a treatment benefit.
Antifibrinolytics such as tranexamic acid and -aminocaproic acid have less efficacy data in the setting of ICH after alteplase administration. Mechanistically, these agents competitively bind to plasminogen, blocking its conversion to plasmin and inhibiting fibrin degradation (Frontera 2016). Supporting data analyses for recommending these agents are limited to case reports and small, retrospective case series. Given the slightly stronger evidence for cryoprecipitate, the NCS guidelines recommend cryoprecipitate over antifibrinolytics unless there is a contraindication to using or significant delay in obtaining this product. The authors state that an antifibrinolytic such as tranexamic acid or -aminocaproic acid can be used as an alternative to cryoprecipitate if these conditions exist. Alternatively, the 2019 AHA/ASA guidelines for the early treatment of patients with AIS are less direct about this recommendation, suggesting that using both agents together could be considered, but certainly antifibrinolytics would have a specific benefit in situations where cryoprecipitate was unavailable or otherwise contraindicated.
Transfusing platelets for the treatment of ICH associated with alteplase remains controversial as well. No data have supported the use of platelet transfusion, regardless of Plt. In fact, in one retrospective study, platelet transfusion was associated with a risk of hematoma expansion; however, given the study's retrospective design, the authors could not
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Acute Ischemic Stroke
Table 6. Management of Symptomatic ICH Within 24 Hr After IV Thrombolytic Administration
AHA/ASA 2019
NCS 2016
Discontinue alteplase
Discontinue thrombolytic infusion when ICH is present or suspected
Obtain CBC, PT (INR), PTT, fibrinogen concentration, type, and cross-match
No recommendation made for pretreatment laboratory tests
Cryoprecipitate 10 units infused over 10?30 min. Administer additional dose if fibrinogen concentration < 200 mg/dL
Cryoprecipitate 10 units initially for patients with thrombolytic administration within previous 24 hr. Administer additional dose if fibrinogen concentration < 150 mg/dL
Tranexamic acid 1000 mg IV over 10 min OR -aminocaproic acid 4?5 g IV over 1 hr, followed by 1 g IV until bleeding controlled (Potential for benefit in all patients, but particularly when blood products are contraindicated or declined by patient/family or if cryoprecipitate is not available in a timely manner)
When cryoprecipitate contraindicated or unavailable in a timely fashion, suggest tranexamic acid 10?15 mg/kg IV over 20 min or -aminocaproic acid 4?5 g IV as an alternative to cryoprecipitate
No recommendation for platelet transfusion
Unclear whether platelet transfusion is useful; therefore, no recommendation offered
Hematology and neurosurgery consultation and supportive therapy, BP management, ICP, CPP, MAP, temperature, and glucose control
No recommendation made for consultations or supportive therapies
AHA/ASA = American Heart Association/ American Stroke Association; BP = blood pressure; CPP = cerebral perfusion pressure; ICH = intracranial hemorrhage; ICP = intracranial pressure; MAP = mean arterial pressure; NCS = Neurocritical Care Society.
Information from: 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; Frontera JA, Lewin JJ, Rabinstein AA, et al. Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for health-care professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care 2016;24:6-46.
conclude whether this finding was because of selection or even outcome bias (Yaghi 2015). Regardless, given the paucity of data with this intervention in ICH after alteplase, the NCS guidelines recommend against the routine use of platelets and make no recommendation about platelet transfusion in known thrombocytopenia.
Additional supportive therapy for ICH after thrombolysis is essentially extrapolated from the management of spontaneous ICH. In-depth discussion is beyond the scope of this chapter. Briefly, SBP should be lowered to a target of less than 160 mm Hg to decrease the risk of further hematoma expansion. Administration of anticoagulation reversal agents such as 4-factor prothrombin complex concentrate and vitamin K should be reserved for patients who were receiving anticoagulants at the time of alteplase administration (Frontera 2016). Administration of hyperosmolar solutions such as hypertonic saline or mannitol may be necessary if cerebral edema or increased intracranial pressure is present or if the patient has signs of impending herniation.
Orolingual angioedema is a rare but important adverse reaction associated with alteplase therapy after AIS. Alteplase is thought to cause angioedema in AIS through several pathways activated by the conversion of plasminogen
into plasmin, resulting in both histamine release and an increase in circulating bradykinin (Hill 2000). The 2019 AHA/ ASA guidelines provide treatment recommendations for alteplase-induced angioedema as outlined in Figure 2.
The incidence of orolingual angioedema is 1%?5%, and concurrent use of angiotensin-converting enzyme inhibitors (ACEIs) is associated with up to 65% of cases. This is thought to be propagated by an already elevated bradykinin in patients receiving ACEI therapy. In most cases associated with alteplase, angioedema is self-limiting and typically does not require an advanced airway. A recent, prospective analysis of 923 patients treated with intravenous alteplase for AIS in a single center in France found an overall incidence of angioedema of 2.2%, with no patients requiring an advanced airway or epinephrine (Myslimi 2016). Outcomes, including 90-day mRS and ICH, did not differ between those who had angioedema and those who did not. The risk of angioedema increased significantly in those receiving ACEI therapy (OR 3.8; 95% CI, 1.6?9.3). No single anatomic site of stroke was linked to the development of angioedema.
The AHA/ASA guidelines recommend blood pressure checks, neurologic examinations, and angioedema screenings every 15 minutes for the first 2 hours after initiating
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Acute Ischemic Stroke
Discontinue alteplase and hold ACEIs
Maintain the airway
? Involvement of the larynx, palate, floor of mouth, or oropharynx with progression within 30 minutes may pose a higher risk of requiring intubation
Treat histamine related angioedema
? Administer methylprednisolone 125 mg intravenously, diphenhydramine 50 mg intravenously, and ranitidine 50 mg or famotidine 20 mg intravenously
? May consider epinephrine 0.3 mg IM or 0.5 mg nebulized if angioedema continues despite above treatment
Consider alternative therapies
? Consider icatibant (a selective bradykinin B2 receptor antagonist), 30 mg subcutaneously or plasma-derived C1 esterase inhibitor 20 IU/kg intravenously
Figure 2. Treatment of alteplase-induced angioedema. C1 = complement 1; IM = intramuscular(ly). Information from: 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.
alteplase and then every 30 minutes for the next 6 hours, followed by every hour until 24 hours after administering intravenous alteplase (Powers 2019; Miller 2010). The AHA/ ASA guidelines also recommend a computed tomography (CT) scan or magnetic resonance imaging (MRI) about 24 hours after alteplase, prior to initiating anticoagulant or antiplatelet agents.
Tenecteplase Tenecteplase is a 3-point-mutated (T-threonine, N-asparagine, K-lysine) variant of alteplase, resulting in an agent with the same mechanism of action but a longer half-life (22 minutes vs. 4 minutes), a 14-fold increased specificity toward fibrin, and an 80-fold increased resistance to plasminogen activator inhibitor-1 compared with alteplase (Logallo 2015). These pharmacokinetic differences allow tenecteplase to be given as a single intravenous push injection rather than as an infusion and create greater specificity of the agent for fibrin-rich clots. These features provide tenecteplase with a more potent and faster fibrinolysis than alteplase. Furthermore, tenecteplase causes less consumption of fibrinogen, plasminogen, and 2-antiplasmin, leading to a lower systemic fibrinolytic effect than that produced by alteplase and, theoretically, a lower bleeding risk (Logallo 2015). The aforementioned pharmacokinetic and pharmacodynamic properties of tenecteplase make it appealing for AIS treatment. To date,
three phase II clinical trials and one phase III randomized clinical trial evaluating tenecteplase in AIS have been published (Table 7). Three additional phase III studies are under way: TASTE (Australian New Zealand Clinical Trials Registry number ACTRN12613000243718), TEMPO-2 ( 2019b; NCT02398656), and TWIST (NCT03181360).
The NOR-TEST study was a phase III, randomized, multicenter, open-label, blinded end point superiority trial in Norway (Logallo 2017). Patients presenting within 4.5 hours of onset or awakening with suspected AIS received either intravenous tenecteplase 0.4 mg/kg (maximum dose 40 mg) or alteplase 0.9 mg/kg (maximum dose 90 mg). Patients awakening with symptoms were eligible to receive tenecteplase on the basis of advanced MRI techniques, to identify a low risk-benefit. The study enrolled 1100 patients, and the baseline demographics did not differ between groups. Patients enrolled had an average age of 71 years, were primarily male, and had mild (NIHSS score 0?7) stroke. Median door-to-needle times (DTNs) were 32 and 34 minutes in the tenecteplase and alteplase groups, respectively. The primary outcome of excellent functional outcome (mRS score of 0 or 1 at 3 months) was achieved at similar rates in patients receiving tenecteplase and alteplase (see Table 7). The rate of ICH did not differ, which occurred in 3% and 2% of patients in the tenecteplase and alteplase groups, respectively (OR 1.16; 95% CI, 0.51?2.68; p=0.70).
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