Ischemic Stroke

Key Points

• Ischemic stroke is an episode of neurologic dysfunction caused by focal cerebral, spinal, or retinal infarction
• Initial physical examination includes a focused neurologic examination, which enables the examiner to obtain a baseline NIH Stroke Scale score. Evaluation must proceed quickly; immediately involve neurologist or stroke team so that patient does not lose eligibility for time-limited treatments
• CT scan (without contrast) is initial imaging modality of choice (in most facilities) to exclude acute hemorrhage; MRI is an alternative ^r1
• If large vessel occlusion is suspected and endovascular mechanical thrombectomy is considered, perform CT angiography or magnetic resonance angiography to image intracranial vessels; this imaging must not delay administration of IV thrombolytic therapy to eligible patients ^r1
• IV thrombolytic is first line therapy and is administered to patients who meet eligibility criteria within 3 hours of symptom onset. This window of time may be stretched to 4.5 hours for patients who meet eligibility criteria ^r1
• Offer endovascular mechanical thrombectomy in addition to IV thrombolytic therapy to eligible patients with infarct attributable to an occluded internal carotid artery or proximal middle cerebral artery, NIH Stroke Scale score of 6 or greater, and good prestroke function
• Selected patients with other causative occlusions who do not meet these criteria also may benefit from endovascular treatment
• Acute ischemic stroke has variable prognosis, based on location and size of the infarct. IV administration of IV thrombolytics and endovascular mechanical thrombectomy improve functional outcomes but increase risk of intracranial bleeding
• Early recognition and management of stroke complications, including cerebral edema and intracranial bleeding, help prevent further brain damage

Urgent Action

• Urgent management of airway, ventilation, and circulation is vital in patients who have decreased levels of consciousness
• Implement institutional stroke code for patients with acute ischemic stroke to administer IV thrombolytics within 4.5 hours of symptom onset, after appropriate screening, with the following goals: ^r2
  • Within 20 minutes of patient arrival: perform CT scan (without contrast) ^r1
  • Determine eligibility for thrombolytic therapy
  • Within 4.5 hours of symptom onset, administer IV thrombolytics ^r1
  • Before initiating IV thrombolytics blood pressure goal should be lower than 185/110 mm Hg, thereafter lower than 180/105 mm Hg
  • Door-to-needle goal for thrombolytic therapy is within 60 minutes; a 45-minute goal is considered reasonable ^r1r2
• For most patients, the only laboratory test result that must be reviewed before administering a thrombolytic agent is fingerstick (or blood-drawn) glucose level
• Selected patients (ie, those with possible bleeding diathesis and those suspected or known to be on anticoagulants) must have their coagulation study results reviewed before being given IV thrombolysis
• If anticipating endovascular therapy, obtain imaging of intracranial vessels with either CT or magnetic resonance angiography during initial brain imaging, if possible ^r1

Pitfalls

• After taking initial history, obtain head CT scan without contrast if ischemic stroke is suspected. Do not waste time waiting for results of other recommended diagnostic testing before initiating thrombolytic therapy in eligible patients, with the following exceptions: ^r1
  • All patients: the only laboratory result required in all patients before thrombolytic therapy is initiated is blood glucose level; fingerstick blood draw is acceptable
  • Patients with known or suspected bleeding diathesis or anticoagulant use: review coagulation studies and platelet count to ascertain eligibility before proceeding
• IV thrombolytic therapy has proven clinical benefit for both severe stroke symptoms and mild (but disabling) stroke symptoms. Do not exclude patients when NIH Stroke Scale score is low but a functionally disabling deficit (eg, isolated aphasia) is present ^r1

Clinical Clarification

• Ischemic stroke is brain, spinal cord, or retinal cell death attributable to ischemia, based on neuropathologic, neuroimaging, and/or clinical evidence of permanent injury

Classification

• By an underlying cause ^r3
  • Lacunar stroke
    • Small, deep (non-cortical) infarct caused by occlusion of a single penetrating artery
    • Often asymptomatic, but accumulation of multiple lacunar infarcts can cause significant disability ^r4
  • Nonlacunar stroke causes
    • Cardioembolism
    • Large artery atherosclerosis
    • Other known causes
    • Cryptogenic (undetermined cause)
      • Includes embolic stroke of unknown source

Clinical Presentation

Acute stroke symptoms in a young patient with neck pain and headache suggest carotid or vertebral dissection as the cause ^c22c23

Note comorbid conditions and medications that may affect decision to administer thrombolytic therapy, including: ^r1

• Current use of warfarin
• Current use of direct thrombin inhibitors or direct factor Xa inhibitors
• Current use of heparin or low-molecular-weight heparins at therapeutic doses
• Head trauma or stroke within past 3 months
• Gastrointestinal or urinary tract bleeding within past 21 days
• Recent (within past 14 days) major trauma or major surgery
• Intracranial or spinal surgery within the past 3 months
• Diagnostic dural or intra-arterial puncture in noncompressible location within past 7 days
• History of intracranial hemorrhage
• Presenting symptoms or signs concerning for subarachnoid hemorrhage
• History of intracranial aneurysm or vascular malformation
• Bleeding or clotting disorder
• Systemic malignancy
• Structural GI malignancy
• Pregnancy
• Infective endocarditis
• Aortic dissection

Symptoms that suggest alternative diagnoses include:

• Fever or recent infection
• Seizures
• Psychiatric disorders
• Migraine with aura

Causes and Risk Factors

Diagnostic Procedures

Differential Diagnosis

Goals

• Start treatment for eligible patients as quickly as possible ^r1
  • A key concept is that a stroke may have a central, irreversibly infarcted core surrounded by a penumbra of critically ischemic tissue for which prompt reperfusion can preserve function - "time is brain" ^r21
  • Door-to-needle goal for thrombolytic therapy is within 60 minutes; within 45 minutes is best
  • Start thrombolytic therapy as soon as possible, but within 4.5 hours of symptom onset or last known to be normal
  • Begin endovascular therapy (with mechanical thrombectomy) as early as possible but within 6 hours; may be considered in select patients up to 24-hour window
  • Technical goal of thrombectomy is reperfusion to a mTICI (modified thrombolysis in cerebral infarction) 2b/2c/3 angiographic result to maximize probability of a good functional clinical outcome
• Prevent complications; recognize and manage existing ones
• Arrange rehabilitation to preserve or improve function
• Prevent recurrence

Disposition

Treatment Options

Initial emergency department/hospital management

• General supportive care
  • Monitor and correct hypoxia, hypo- or hyperglycemia, and hyperthermia; correction may be associated with improved outcomes ^r24
    • Supplemental oxygen is not recommended in nonhypoxic patients; use supplemental oxygen only to maintain saturation higher than 94% (94%-96% recommended^r25) ^r1
    • Intubation may be required in patients with decreased respiratory drive owing to cerebral edema or hemispheric stroke
      • Also recommended for those who have bulbar dysfunction that causes airway compromise
    • Treat hyperglycemia to achieve blood glucose target of 140 to 180 mg/dL (must be less than 400 mg/dL to proceed to thrombolytic therapy); treat hypoglycemia if below 60 mg/dL (must be higher than 50 mg/dL to proceed to thrombolytic therapy) ^r1
    • If patient is febrile, administer antipyretics to maintain body temperature lower than 38 °C ^r1r26
    • There is no role for therapeutic hypothermia ^r27
  • Correct hypotension and hypovolemia to maintain systemic perfusion ^r1
    • Optimal blood pressure and parenteral fluid type and volume are unknown
  • Position patient
    • Patients traditionally were placed flat in bed for the first 24 hours unless there was risk of aspiration or suspected increased intracranial pressure; however, a recent trial showed no significant 90-day disability difference between lying flat and sitting up with head elevated at least 30° ^r28
  • Do not administer any oral medications until patient is screened for swallowing dysfunction. Administer medications by alternative routes ^r1
• Acute blood pressure management
  • Goal blood pressure
    • Optimal blood pressure in acute stroke is unknown; in general:
      • There may be an association between worse outcomes and lower blood pressures, but not all studies confirm this
      • Limited studies have addressed treatment of low blood pressure in patients with stroke; benefits and harms of crystalloids versus colloids to treat hypotension are unknown ^r1
    • If patient is eligible for reperfusion therapies
      • Lower blood pressure to lower than 185/110 mm Hg before thrombolytic therapy and maintain at lower than 180/105 mm Hg for 24 hours afterward ^r1r29
        • Exact blood pressure at which risk of hemorrhage after thrombolysis increases is unknown. These recommendations are based on target blood pressures used in randomized controlled trials of IV thrombolytic therapy ^r30
        • No specific minimum systolic blood pressure is recommended with thrombolytic therapy, but systolic pressures between 141 and 150 mm Hg have been associated with optimal mortality and functional outcomes ^r31
      • For patients undergoing mechanical thrombectomy, it is recommended to maintain blood pressure below 180/105 mm Hg during thrombectomy and for 24 hours afterward ^r32
        • After successful thrombectomy, intensive blood pressure control (systolic blood pressure less than 140 mmHg) compared to standard therapy (systolic blood pressure less than 180 mmHg) may be associated with worse functional outcomes ^r33
      • Choice of blood pressure treatment for patients eligible for thrombolytic therapy
        • Fast-acting, rapidly reversible agents are recommended
          • Recommended treatments include labetalol, nicardipine, clevidipine, and sodium nitroprusside ^r1
            • Other options may be appropriate for patients with comorbid conditions that may benefit from acute reductions in blood pressure (eg, acute coronary event, acute heart failure, aortic dissection, preeclampsia, eclampsia)
            • If blood pressure is not maintained at 185/110 mmHg or lower, do not administer IV thrombolytics
            • During and after thrombolytic therapy, maintain blood pressure at 180/105 mm Hg or lower
    • If the patient is not eligible for thrombolytic therapy and has very high blood pressure (higher than 220 mm Hg systolic or 120 mm Hg diastolic) careful blood pressure reduction is reasonable ^r1r29r32
      • May be lowered by 15% within 24 hours of symptom onset; watch for worsening of neurologic function
      • Acute lowering (in the first 24 hours) is not necessary if blood pressure is lower than 220/120 mm Hg, unless the patient has another condition that requires it (eg, acute coronary syndrome, aortic dissection, hypertensive encephalopathy) ^r32
      • Blood pressure management is more permissive to promote collateral vessel perfusion

Begin reperfusion therapy for eligible patients (those who meet all general eligibility criteria and do not have contraindications) as soon as possible

• Thrombolysis with an IV recombinant tissue plasminogen activator for eligible patients. Door-to-needle time of 60 minutes is the goal^r2; 2019 guidelines suggested 45 minutes may be achievable. Give this treatment even if considering endovascular therapies^r1
  • A 2020 study reported that among patients aged 65 years or older with acute ischemic stroke who were treated with tissue plasminogen activator, shorter door-to-needle times were associated with lower all-cause mortality and lower all-cause readmission at 1 year ^r34
  • Owing to the proven benefit and need to expedite treatment, when a patient cannot provide consent (eg, has aphasia or confusion) and a legally authorized representative is not immediately available to provide proxy consent, it is justified to proceed with IV thrombolysis in an otherwise eligible adult patient with a disabling acute ischemic stroke ^r1
  • If inhouse expertise is unavailable, telestroke networks may be helpful for triaging patients who are eligible for thrombolysis or interfacility transfer for acute mechanical thrombectomy
  • First line therapy
    • 2019 American Heart Association/American Stroke Association^r1 and 2021 European Stroke Association^r35 guidelines recommend alteplase as first line therapy; IV tenecteplase is a reasonable alternative in patients who are eligible for both IV fibrinolysis and mechanical thrombectomy and in those with minor neurologic impairment and no major intracranial occlusion
    • 2023 European Stroke Association guidelines now state that tenecteplase is equally safe and effective to alteplase for all thrombolytic-eligible patients who are less than 4.5 hours post acute ischemic stroke ^r36
      • Compared to alteplase, tenecteplase is less expensive and easier to administer (does not require a 1 hour infusion after the bolus dose)
      • Tenecteplase is recommended over alteplase for patients with acute ischemic stroke with large vessel occlusion presenting within 4.5 hours of symptom onset ^r36
  • Eligibility and timing
    • When it can be administered within 3 hours of stroke symptom onset or from baseline status (time last known to be well), offer IV thrombolytics to all otherwise eligible patients aged 18 years or older who have a quantifiable neurologic deficit ^r1
      • Equally recommended for patients aged 80 years or older ^r35
      • Recommended for both severe stroke symptoms and mild but disabling stroke symptoms ^r35
        • There is increased risk of hemorrhagic transformation with severe stroke symptoms, but there is still proven clinical benefit for these patients when treatment is administered in 3-hour time window
      • Not recommended for otherwise eligible patients with mild nondisabling stroke
    • When it can be administered in the 3- to 4.5-hour window, offer IV thrombolysis to all otherwise eligible patients aged 18 to 80 years ^r1
      • Lower-level evidence suggests that for patients older than 80 years presenting in the 3- to 4.5-hour window, IV alteplase is safe and can be as effective as it is in younger patients ^r35
      • In this time window, patient must meet these additional criteria:
        • NIH Stroke Scale score 25 or less (benefit uncertain with higher score)
        • No imaging evidence of ischemic injury involving more than one-third of middle cerebral artery territory
        • Not taking any oral anticoagulants; however, for patients taking warfarin who have an INR of 1.7 or lower and present in the 3- to 4.5-hour window, IV thrombolytics appears safe and may be beneficial ^r1
    • When it can be administered within 4.5 hours of stroke symptom recognition, alteplase also may be beneficial in otherwise eligible patients aged 18 to 80 years who awaken with stroke symptoms or who have unclear time of onset and have diffusion-weighted MRI findings of a lesion involving less than one-third of the middle cerebral artery territory and no visible signal change on FLAIR (fluid-attenuated inversion recovery) ^r1
    • 2021 European Stroke Association guidelines also recommend intravenous thrombolysis with alteplase for patients presenting from 4.5 to 9 hours after known onset time or those with stroke symptoms on awakening from sleep, and with CT or MRI evidence of core/perfusion mismatch, and for whom mechanical thrombectomy is either not indicated or not planned ^r35
  • Contraindications to intravenous thrombolysis ^r1
    • Mild nondisabling stroke
    • Hypertension that cannot be lowered to under 185/110 mm Hg ^r35
    • CT scan showing acute intracranial hemorrhage
    • CT scan showing extensive regions of clear hypoattenuation (these patients have a poor prognosis despite IV alteplase; severe hypoattenuation defined as obvious hypodensity represents irreversible injury)
    • Ischemic stroke within past 3 months
    • Severe head trauma within past 3 months
      • Do not administer IV thrombolytics to patient with posttraumatic infarction that occurs during the acute in-hospital phase of management of head trauma
    • Intracranial/spinal surgery within previous 3 months
    • Earlier history of intracranial hemorrhage
    • Symptoms and signs most consistent with a subarachnoid hemorrhage
    • Patients with structural gastrointestinal malignancy or gastrointestinal bleeding event within 21 days of stroke event are considered high risk
    • Coagulopathy
      • Platelet count lower than 100,000 cells/mm³
        • In patients without history of thrombocytopenia, can initiate treatment with alteplase before platelet count is available, but discontinue alteplase if platelet count is lower than 100,000 cells/mm³
      • Any of the following: INR higher than 1.7, prothrombin time greater than 15 seconds, or activated partial thromboplastin time greater than 40 seconds
        • In patients who have not recently used oral anticoagulants or heparin, initiate treatment with IV thrombolytics before coagulation test results are available, but discontinue treatment if INR is higher than 1.7 or prothrombin time is abnormally elevated by local laboratory standards
    • Concomitant medications
      • Direct thrombin inhibitors or direct factor Xa inhibitors: do not administer tissue plasminogen activator unless laboratory test results (eg, activated partial thromboplastin time, INR, platelet count, ecarin clotting time, thrombin time, appropriate direct factor Xa activity assays) are within reference range or unless patient has not received a dose of these agents for more than 48 hours
      • Low-molecular-weight heparin: do not administer tissue plasminogen activator to patients who have received a full treatment dose (not prophylactic dose) of low-molecular-weight heparin within the previous 24 hours
    • Known intra-axial intracranial neoplasm
    • Known or suspected aortic arch dissection
    • Symptoms consistent with infective endocarditis

    • Contraindications to IV thrombolysis.

      Data from Powers WJ 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. 50(12):e344-418, 2019.

      Category of contraindication	Contraindication
      General
      Time of symptom onset	Time of symptom onset is unclear or was not witnessed in a patient whose last known time at baseline state is more than 3 to 4.5 hours prior
      	More than 4.5 hours since time of stroke symptom onset or when patient was last known to be well/at baseline
      Hypo- and hyperglycemia	Do not administer alteplase until hypoglycemia corrected to greater than 50 mg/dL and hyperglycemia corrected to less than 400 mg/dL
      Blood pressure	Hypertension that cannot be lowered to less than 185/110 mm Hg
      Alternative or comorbid critical diagnosis	Patient presentation suggests subarachnoid hemorrhage
      	Known or suspected aortic arch dissection
      	Symptoms consistent with infective endocarditis
      Imaging
      CT reveals	Acute intracranial hemorrhage
      	Extensive regions of clear hypoattenuation
      Past medical history and comorbidities
      Recent history, within past 3 months	Prior ischemic stroke
      	Severe head trauma
      	Intracranial/spinal surgery
      Known history	Intracranial hemorrhage
      Comorbidity	Intra-axial intracranial neoplasm
      	Patients with structural gastrointestinal malignancy or recent gastrointestinal bleeding event within 21 days of their stroke event should be considered high risk
      Coagulopathy/anticoagulant use
      Platelets	Less than 100,000 cells/mm³
      INR and prothrombin time	INR greater than 1.7; Prothrombin time greater than 15 seconds (or abnormal by local standards); and/or activated partial thromboplastin time greater than 40 seconds
      Warfarin use	Patients with a history of warfarin use, unless INR is 1.7 or less and/or a prothrombin time is less than 15 seconds, in which case treatment may be reasonable
      Direct thrombin inhibitors or direct factor Xa inhibitors	Unless results of laboratory tests such as activated partial thromboplastin time, INR, platelet count, ecarin clotting time, thrombin time, or appropriate direct factor Xa activity assays are normal, or the patient has not received a dose of these agents for greater than 48 hours
      Low-molecular-weight heparin	Patients who have had full treatment dose (not prophylactic dose) within the previous 24 hours

  • Other eligibility considerations
    • The following statements are largely based on studies using alteplase; their applicability to use of tenecteplase is uncertain
    • Warfarin: IV alteplase appears safe and may be beneficial for patients taking warfarin who have an INR of 1.7 or lower and present within the 4.5-hour window ^r1
    • Hypo- and hyperglycemia may mimic acute stroke presentations; do not administer alteplase until hypoglycemia is corrected to glucose levels greater than 50 mg/dL and hyperglycemia corrected to glucose lower than 400 mg/dL ^r1
      • European guidelines do not recommend withholding alteplase in patients with blood glucose greater than 400 mg/dL despite the risk of poor functional outcome in such patients ^r35
    • Dural puncture: may consider IV alteplase for patients who present with acute ischemic stroke, even when they have undergone a lumbar dural puncture in the preceding 7 days ^r1
    • Arterial puncture: safety and efficacy of administering IV alteplase to patients who present with acute ischemic stroke who have had an arterial puncture of a noncompressible blood vessel in the 7 days preceding stroke symptoms are uncertain ^r1
    • Recent major trauma: in patients with acute ischemic stroke and recent major trauma (within 14 days) not involving the head, carefully consider IV alteplase, but weigh risks of bleeding from injuries related to trauma against severity and potential disability from ischemic stroke ^r1
    • Recent major surgery: consider using IV alteplasein carefully selected patients presenting with acute ischemic stroke who have undergone a major surgery in the preceding 14 days, but weigh potential increased risk of surgical site hemorrhage against anticipated benefits ^r1
    • Past gastrointestinal/genitourinary bleeding (more than 21 days before): literature reports low bleeding risk with IV alteplase administered in the setting of past gastrointestinal/genitourinary bleeding. Administering IV alteplase in this patient population may be reasonable (alteplase administration within 21 days of a gastrointestinal bleeding event is not recommended) ^r1
    • Menstruation: IV alteplase is probably indicated in women who present with acute ischemic stroke who are menstruating and do not have a history of menorrhagia. Warn patients that alteplase treatment could increase menstrual flow ^r1
      • Consider IV thrombolytics because potential benefits probably outweigh serious bleeding risks even in patients with recent history of or active menorrhagia who do not have clinically significant anemia or hypotension
      • When there is history of or recent active vaginal bleeding that causes clinically significant anemia, emergency consultation with a gynecologist is indicated before making a decision about IV thrombolytics
    • Cervical dissections ^r1
      • Intracranial: usefulness and hemorrhagic risk of alteplase with known or suspected associated intracranial arterial dissection remain unknown, uncertain, and not well established
      • Extracranial: when stroke is suspected to be associated with extracranial cervical arterial dissection, alteplase is reasonably safe when given within 4.5 hours and probably recommended
    • Cerebral microbleeds
      • In otherwise eligible patients who have previously demonstrated a small number (1-10) of cerebral microbleeds on MRI, administer IV thrombolytics ^r1
      • In otherwise eligible patients who have previously demonstrated a high burden of cerebral microbleeds (more than 10) on MRI, IV thrombolytics may be associated with increased risk of intracranial hemorrhage and benefits of treatment are uncertain; however, IV thrombolytics may be reasonable if there is potential for significant benefit ^r1
    • Unruptured intracranial aneurysm: with a known small or moderate (less than 10 mm) unruptured and unsecured intracranial aneurysm, IV alteplase is probably recommended ^r1
    • Extra-axial intracranial neoplasm: alteplase treatment is probably recommended for patients with acute ischemic stroke who harbor an extra-axial intracranial neoplasm ^r1
    • Acute or recent myocardial infarction ^r1
      • Acute myocardial infarction: for patients presenting with concurrent acute ischemic stroke and acute myocardial infarction, treat with IV alteplase at the dose appropriate for cerebral ischemia and follow with percutaneous coronary angioplasty and stenting, if indicated
      • Recent myocardial infarction (within 3 months):
        • Non–ST elevation myocardial infarction: treat ischemic stroke with IV alteplase
        • ST elevation myocardial infarction involving the right or inferior myocardium: treat ischemic stroke with IV alteplase
        • ST elevation myocardial infarction involving the left anterior myocardium: treat ischemic stroke with IV alteplase
    • Procedural stroke: depending on eligibility criteria, treat ischemic stroke complications of cardiac or cerebral angiographic procedures with IV alteplase ^r1
    • Systemic malignancy: patients with systemic malignancy and life expectancy longer than 6 months may benefit from IV alteplase if other contraindications (eg, coagulation abnormalities, recent surgery, systemic bleeding) do not coexist ^r1
    • Pregnancy or postpartum period ^r1
      • During pregnancy: consider administering IV alteplase when anticipated benefits of treating moderate or severe stroke outweigh anticipated increased risks of uterine bleeding
      • Early postpartum period (less than 14 days after delivery): safety and efficacy of IV alteplase have not been well established
    • Ophthalmic conditions: can use IV alteplase in patients presenting with acute ischemic stroke who have a history of diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions, but weigh potential increased risk of vision loss against anticipated benefits of reduced stroke-related neurologic deficits ^r1
    • Sickle cell disease: IV alteplase can be beneficial for adults presenting with an acute ischemic stroke who have known sickle cell disease ^r1
    • Illicit drug use: drug use can contribute to incident stroke; IV alteplase may be used in patients with illicit drug use–associated acute ischemic stroke if they have no other exclusions ^r1
    • Conditions that mimic stroke (eg, postictal paresis, migraine): risk of symptomatic intracranial hemorrhage in patients with these conditions is quite low. Recommended to start IV alteplase rather than delaying treatment to pursue additional diagnostic studies ^r1
• Endovascular therapy with mechanical thrombectomy is recommended for eligible patients; reduced time from symptom onset to reperfusion with endovascular therapies is highly associated with better clinical outcomes ^{r37r38r39r40r41r42}
  • Mechanical thrombectomy with stent retrievers is the recommended first line therapy ahead of intra-arterial fibrinolysis ^r1
    • Intra-arterial fibrinolysis within 6 hours of stroke symptom onset may be considered in selected patients with contraindications to IV thrombolysis; however, outcomes are unknown
    • Aspiration thrombectomy (eg, A Direct Aspiration, First Pass Technique [ADAPT]) may have safety and efficacy similar to stent-retrieval thrombectomy for acute ischemic stroke ^r43
  • Administer an IV thrombolytic to eligible patients even if considering mechanical thrombectomy ^r1
    • The benefits to outcome of adding thrombolysis to thrombectomy are time dependent and may not be seen if given more than 3 hours after onset of symptoms ^r44
  • Do not postpone endovascular therapy to await/monitor for clinical response after administering an IV thrombolytic ^r1r45
  • Eligibility and timing
    • Patients should receive mechanical thrombectomy with a stent retriever if treatment can be initiated (groin puncture) within 6 hours of symptom onset and they meet all the following criteria:
      • Prestroke modified Rankin Scale score of 0 to 1 ^r1
        • Although benefits are uncertain, may be considered for patients who have prestroke modified Rankin Scale score greater than 1 and causative occlusion of the internal carotid artery or proximal middle cerebral artery (M1); additional randomized trial data are needed
      • Causative occlusion of the internal carotid artery or middle cerebral artery segment 1 (M1) ^r1
        • Although benefits are uncertain, also may be considered for patients who have 1 of the following:
          • Causative occlusion of the middle cerebral artery segment 2 (M2) or middle cerebral artery segment 3 (M3)
          • Causative occlusion of the anterior cerebral arteries, vertebral arteries, basilar artery^r46, or posterior cerebral arteries
      • Patient aged 18 years or older
        • Meta-analysis of 5 randomized controlled trials showed favorable effect with mechanical thrombectomy over standard care across all patient age subgroups including those aged 70 years or older (number of patients in these trials who were aged 90 years or older was very small) ^r47
      • NIH Stroke Scale score of 6 or greater ^r1
        • Although benefits are uncertain, may be considered for patients who have prestroke NIH Stroke Scale score less than 6 and causative occlusion of the internal carotid artery or proximal middle cerebral artery (M1); additional randomized control trial data are needed
      • ASPECTS (Alberta Stroke Program Early CT Score) of 6 or greater ^r1
        • Although benefits are uncertain, may be considered for patients who have ASPECTS (Alberta Stroke Program Early CT Score) less than 6 and causative occlusion of the internal carotid artery or proximal middle cerebral artery (M1); additional randomized trial data are needed
    • If treatment can be initiated (groin puncture) within 6 to 16 hours of time last known to be well, mechanical thrombectomy is recommended in selected patients with both of the following: ^r1
      • Large vessel occlusion in the anterior circulation
      • Meeting other eligibility criteria from DAWN^r48 or DEFUSE 3^r49 trial
    • If treatment can be initiated (groin puncture) within 16 to 24 hours of time last known to be well, mechanical thrombectomy is reasonable in selected patients with both of the following: ^r1
      • Large vessel occlusion in the anterior circulation
      • Meeting other eligibility criteria from DAWN ^r48trial
  • Salvage intra-arterial thrombolysis may be used to achieve desired mTICI 2b/2c/3 angiographic result (on the modified treatment in cerebral infarction scale) ^r1
  • Outcomes with endovascular thrombectomy surpass those of standard IV thrombolytic therapy ^r50
    • Functional outcomes in patients with acute anterior circulation ischemic stroke and large artery occlusion are superior to those attained with standard therapy ^r51
    • Neurologic outcomes are superior 3 months after treatment in patients who receive endovascular treatment in addition to IV thrombolysis ^r52
    • For patients with severe stroke, adding endovascular interventions improves functional outcome and health-related quality of life at 12 months compared with IV thrombolytic therapy alone ^r53

Other initial treatment considerations

• Aspirin
  • Recommended to administer aspirin within 24 to 48 hours after onset of acute ischemic stroke if intracranial hemorrhage has been excluded on follow-up brain CT scan or MRI ^r1r22
  • For patients with minor ischemic stroke (nondisabling and NIH Stroke Scale score of 3 or less) who did not receive an IV thrombolytic, dual antiplatelet therapy with aspirin and clopidogrel beginning within 24 hours is recommended to prevent early secondary stroke ^{r1r3r54r55r56}
    • Treat for 21 days with dual antiplatelet therapy (aspirin and clopidogrel), then continue with antiplatelet monotherapy ^r54r56r57
      • 2021 American Heart Association/American Stroke Association guidelines recommend dual therapy for 30 to 90 days, noting that optimal duration is not known ^r3
    • A meta-analysis found that aspirin plus ticagrelor had similar 3 month efficacy as aspirin plus clopidogrel at preventing recurrent stroke or death in patients with minor ischemic stroke, though aspirin plus clopidogrel was associated with slightly lower rates of functional disability (hazard ratio 0.82 vs 0.85) ^r58
    • Delayed initiation (more than 7 days after index event) or extended duration (more than 90 days after index event) of dual antiplatelet therapy is no more effective than a single agent for ischemic stroke prevention and increases the risk of bleeding ^r3r54r59
    • European guidelines and American Heart Association/American Stroke Association 2021 secondary stroke prevention guidelines also recommend dual antiplatelet therapy with aspirin and ticagrelor for 30 days for patients with non-cardioembolic mild to moderate ischemic stroke in the past 24 hours (weaker recommendation) ^r3r54r60
    • Do not use dual antiplatelet therapy in patients with major stroke owing to increased risk of intracranial bleeding ^r56
  • For those treated with an IV thrombolytic, delay aspirin administration until 24 hours later ^r1
  • In patients unsafe or unable to swallow, rectal or nasogastric administration is appropriate ^r22
  • Safety and benefit confirmed by a large Cochrane review of aspirin trials ^r61
  • Aspirin is not a substitute for acute stroke treatment in patients who are eligible for IV thrombolysis or mechanical thrombectomy ^r1
  • Continue aspirin or initiate alternative antithrombotic agent 2 weeks after stroke or discharge (whichever is sooner) ^r22
• Deep venous thrombosis prophylaxis
  • In immobile patients with stroke who do not have contraindications, intermittent pneumatic compression in addition to routine care (aspirin and hydration) is recommended (do not use elastic compression stockings) ^r1
  • Benefit of prophylactic-dose subcutaneous unfractionated or low-molecular-weight heparin in immobile patients with acute ischemic stroke is not well established ^r1
    • Appears to decrease risk of deep venous thrombosis in hospitalized patients with acute ischemic stroke but increases risk of intracranial bleeding ^r62
• Emergency carotid endarterectomy or carotid angioplasty
  • Use of emergent or urgent carotid endarterectomy is not well established ^r1
  • Stroke specialists may consider carotid endarterectomy when clinical indicators or brain imaging suggest a small infarct core with large territory at risk (eg, penumbra), compromised by inadequate flow from a critical carotid stenosis or occlusion
• Urgent anticoagulation ^r1
  • Not recommended for preventing early recurrent stroke, halting neurologic worsening, or improving outcomes
  • Meta-analyses confirm the lack of benefit of urgent anticoagulation ^r63r64
  • Usefulness of argatroban, dabigatran, or other thrombin inhibitors to treat patients with acute ischemic stroke is not well established; further clinical trials are needed ^r1
  • Safety and usefulness of factor Xa inhibitors to treat acute ischemic stroke are not well established; further clinical trials are needed ^r1
  • Optimal medical management of patients with radiologic evidence of nonocclusive, intraluminal thrombus (eg, cervical carotid, vertebrobasilar arteries) remains uncertain ^r1
  • Usefulness of urgent anticoagulation in patients with severe stenosis of an internal carotid artery ipsilateral to an ischemic stroke is not well established ^r1
• Neuroprotective or neurorehabilitative agents
  • Various drugs with neuroprotective properties have been studied in preclinical or clinical trials in ischemic stroke; however to date, none has demonstrated consistent benefits ^{r21r65r66r67r68}
    • The Stroke Preclinical Assessment Network in the United States will evaluate several promising neuroprotective agents for efficacy as adjuncts to endovascular thrombectomy ^r65
  • Agents that stimulate endogenous neuroplasticity may help reduce disability after stroke
    • European guideline recommends considering cerebrolysin in conjunction with early motor rehabilitation; citalopram may also be beneficial ^r69

Secondary prevention of stroke

• Effective secondary prevention requires timely identification of stroke mechanism and modifiable risk factors ^r3
• Antihypertensive therapy ^d4
  • American and European guidelines recommend a target blood pressure less than 130/80 mmHg, based on studies showing significantly reduced risk of recurrent stroke compared to a standard blood pressure target of 140/90 mmHg ^r3r70
  • Individualize pharmacologic therapy based on pharmacologic properties, mechanism of action, and specific patient characteristics; a thiazide diuretic, an ACE inhibitor, or an angiotensin receptor blocker may be beneficial ^r3r29
• Antiplatelet therapy
  • Continue antiplatelet drugs during remaining hospitalization and after discharge for secondary prevention in patients with noncardioembolic stroke ^r22r54
  • Individualize drug therapy with aspirin, clopidogrel, ticagrelor, or aspirin-dipyridamole ^r3r71
  • Dual antiplatelet therapy with aspirin and clopidogrel is not recommended for long-term secondary prevention after stroke ^r3
  • Dual antiplatelet therapy with aspirin and clopidogrel for 21 through 90 days beginning within 24 hours is recommended to prevent early secondary stroke in patients with minor ischemic stroke (nondisabling and NIH Stroke Scale score of 3 or less) who did not receive IV alteplase ^r3r54
  • Dual antiplatelet therapy with aspirin and clopidogrel for 90 days is recommended to prevent secondary stroke in patients with intracranial atherosclerosis ^r3
• Statin therapy ^d10
  • Recommended for secondary prevention of stroke; may also improve functional outcomes after acute stroke ^r1
  • According to 2021 guideline, administer atorvastatin 80 mg daily to patients with LDL-C greater than 100 mg/dL and without known coronary artery disease or cardiac causes of embolism ^r3
    • Administer statin therapy (plus ezetimibe if needed) to patients with atherosclerotic disease with goal of reducing LDL-C to less than 70 mg/dL ^r3r70
    • Patients at very high risk (stroke plus one other major atherosclerotic cardiovascular disease event or stroke and multiple high-risk conditions) whose LDL-C remains greater than 70 mg/dL despite maximally tolerated statin therapy and ezetimibe may be treated with a PCSK9 inhibitor ^r3
  • 2019 guidelines recommended patients aged 75 years or younger with clinical atherosclerotic cardiovascular disease receive high-intensity statin therapy (goal of reducing LDL-C levels by at least 50%) ^r1r72
    • Moderate-intensity statin therapy (goal of reducing LDL-C levels by 30%-49%) is appropriate if high-intensity therapy is contraindicated or not tolerated ^r1r72
    • Consider adding ezetimibe to maximally tolerated statin therapy in patients at very high risk (multiple major atherosclerotic cardiovascular disease events or 1 major atherosclerotic cardiovascular disease event and multiple high-risk conditions) and those with suboptimal response to maximally tolerated statin therapy ^r1r72
    • Patients aged older than 75 years with clinical atherosclerotic cardiovascular disease may be given high-intensity or moderate-intensity statin therapy depending on potential benefits, risks, drug interactions, and patient frailty and preferences ^r1r72
  • Continue statin therapy in patients who were already receiving it at time of stroke ^r1
  • For patients who are eligible, consider starting statin therapy in the hospital ^r1
• Oral anticoagulation
  • Long-term direct acting oral anticoagulants (apixaban, edoxaban, dabigatran, rivaroxaban) are indicated for patients with nonvalvular atrial fibrillation ^r3
  • Long-term oral anticoagulation (warfarin) is indicated for patients with valvular atrial fibrillation and with mechanical heart valves ^r3r73d11
    • Warfarin or apixaban (dose adjusted) is indicated for stroke patients with nonvalvular atrial fibrillation and end stage renal disease or on dialysis ^r3
  • Warfarin, dabigatran, rivaroxaban, or apixaban may be used in patients with atrial fibrillation and dilated cardiomyopathy or rheumatic valve disease ^r73r74
• Smoking cessation ^r3d12
  • Advise all patients to avoid exposure to tobacco smoke; advise those who use tobacco to quit (at each contact)
  • May receive assistance in quitting through referral to smoking cessation program or via pharmacotherapy
• Revascularization for carotid artery stenosis
  • Carotid endarterectomy is recommended for patients who have suffered a stroke within 6 months and have ipsilateral severe carotid artery stenosis (70%-99% by noninvasive imaging), provided that mortality and morbidity risk is less than 6% ^r3
    • Also recommended in patients with moderate carotid stenosis (50%-69%) depending on their age, sex, and comorbidities
    • Carotid artery stenting may be considered as an alternative in patients aged younger than 70 years with symptomatic (50%-99%) carotid stenosis and for patients with comorbidities that increase the risks of surgery ^r3r6
    • When revascularization is indicated for nondisabling stroke, it is recommended to perform within 2 weeks of the index stroke ^r3r6
  • Revascularization is not recommended if degree of carotid stenosis is less than 50% ^r3
• Left atrial appendage occlusion ^r75
  • Transcatheter left atrial appendage occlusion is an emerging alternative for stroke prophylaxis in selected patients with nonvalvular atrial fibrillation who are ineligible for long-term anticoagulation ^r3r76

Monitoring

• Follow up with CT scan or MRI 24 hours after thrombolytic therapy before starting anticoagulants or antiplatelet agents ^r1

Complications

• Early recognition and management of acute stroke complications help prevent further brain injury
  • Cerebral edema ^c189c190
    • Patients with large territorial supratentorial infarctions are at high risk for complicating brain edema and increased intracranial pressure
    • Consider early transfer of patients who are at risk for malignant brain edema to institution with neurosurgical expertise ^r1
    • Decline in level of consciousness is most common presentation; timing varies ^r91
      • This symptom is more commonly caused by displacement of midline structures (eg, thalamus, brainstem) than by globally increased intracranial pressure
      • Edema peaks 3 to 4 days after stroke
      • In some patients, may be delayed up to day 10, corresponding to infarction and edema of penumbral area surrounding ischemic tissue
      • Less commonly, early reperfusion of a large volume stroke can cause accelerated edema within the first 24 hours (malignant edema)
    • Other physical signs include ipsilateral pupillary dysfunction, varying degrees of mydriasis, and worsening motor function
    • Confirm with CT scan (preferred; without contrast) or MRI
    • Manage with medical efforts to reduce intracranial pressure while consulting with neurosurgeon ^r91
      • Raise head of bed 20° to 30°
      • Provide brief, moderate hyperventilation as a bridge to more definitive therapy
      • Osmotic therapy with hypertonic saline and mannitol ^r1r91
    • Drains and decompressive surgery may be needed ^r1
      • Can manage acute hydrocephalus that may develop secondary to ischemic stroke by placing ventricular drain ^c191
      • Suboccipital craniectomy may be indicated in patients with large cerebellar strokes causing obstructive hydrocephalus or brainstem compression
      • Decompressive hemicraniectomy may be indicated in patients with massive hemispheric infarctions and declining levels of consciousness (convincing evidence of improved mortality and functional outcome, especially in patients aged younger than 60 years who can be treated within 48 hours of stroke onset) ^r92
  • Intracranial hemorrhage ^r1c192
    • Presents clinically with worsening neurologic symptoms, decreasing mental status, headache, increased blood pressure and pulse, and vomiting
    • May develop within 12 to 24 hours of IV thrombolytic therapy
    • Also may occur in patients who did not receive thrombolytic therapy, especially those who have had more severe strokes, are older, and have a cardioembolic pathogenesis
    • If suspected: ^r1
      • Stop infusion of alteplase
      • Obtain CBC, prothrombin time (INR), activated partial thromboplastin time, fibrinogen level, and type and crossmatch
      • Obtain emergency nonenhanced head CT
      • Administer reversal agents, including cryoprecipitate and aminocaproic acid or tranexamic acid
      • Obtain neurosurgery and hematology consults
      • Provide supportive care, including managing systemic and intracranial pressure
      • Further management depends on size and location of hemorrhage and patient's medical and neurologic status
  • Orolingual angioedema associated with IV alteplase administration ^r1c193
    • Uncommon; manage as follows:
      • Maintain airway
      • Endotracheal intubation may not be necessary if edema is limited to anterior tongue and lips. If needed, awake fiberoptic intubation is optimal
        • Cricothyroidotomy is rarely needed and is also problematic after IV alteplase
      • Discontinue alteplase infusion (and hold any ACE inhibitors)
      • Administer IV methylprednisolone, IV diphenhydramine, and IV famotidine
      • If there is further increase in angioedema, administer epinephrine subcutaneously or by nebulizer
      • Additional treatments that may be beneficial (have been successfully used in hereditary angioedema and ACE inhibitor–related angioedema):
        • Icatibant, a selective bradykinin β₂ receptor antagonist
        • Plasma-derived C1 esterase inhibitor
  • Seizures
    • Manage seizures that occur after ischemic stroke with anticonvulsants, as would be given for any other acute neurologic condition ^r1c194
    • Prophylactic anticonvulsants are not recommended ^r1r93
• Long-term complications after stroke
  • Immobilized patients are at increased risk for developing deep vein thrombosis and pulmonary embolism; anticoagulant prophylaxis for deep vein thrombosis is recommended in these patients ^c195c196
  • Spasticity; managed with stretching exercises, drugs, botulinum toxin injections, and casts ^c197
  • Chronic immobility may predispose these patients to decubitus ulcers (ie, pressure sores, bed sores); regular dressing and treatment of infection may be required ^c198
  • Depression occurs in approximately 30% of patients after stroke ^r94c199
  • Poststroke cognitive impairment is common and may be disabling ^r95c200
  • Ongoing functional impairments; refer to appropriate rehabilitation services ^r96c201c202
  • Dysphagia ^r79c203
  • Risk of falls ^r96c204

Prognosis

• Prognosis for acute ischemic stroke varies based on location and size of infarct
• IV thrombolytic therapy with recombinant tissue plasminogen activator improves neurologic and functional outcome of patients with ischemic stroke treated within 4.5 hours after symptom onset, but it is not associated with a mortality benefit ^r1
• Endovascular therapy using stent retrievers additionally improves outcomes for ischemic stroke resulting from large vessel occlusion; clinical outcome improves with increasing degree of vessel recanalization ^r1
• Symptomatic intracerebral hemorrhage is a complication of IV thrombolysis in a small percentage of patients (3.3% in recent meta-analysis; 6% in other studies); mortality rate may be 50% if this occurs ^r97

Screening ^c205

Prevention

• General recommendations for primary prevention of cardiovascular disease ^r99
  • Perform 10-year atherosclerotic cardiovascular disease risk estimation using a risk estimator tool for adults who are aged 40 to 75 years and are being evaluated for cardiovascular disease prevention; for adults aged 20 to 39 years, it is reasonable to assess traditional risk factors at least every 4 to 6 years
    • A free risk calculator with advice based on recent American College of Cardiology/American Heart Association guidelines is available from the American College of Cardiology (available as web download or app) ^r100
  • All adults should consume a healthy diet that:
    • Emphasizes vegetables, fruits, nuts, whole grains, lean vegetarian or animal protein, and fish
    • Minimizes trans fats, processed meats, refined carbohydrates, and sweetened beverages
  • For adults who are overweight or obese, counseling and caloric restriction are recommended for achieving and maintaining weight loss
  • Adults should engage in at least 150 minutes per week of accumulated moderate-intensity physical activity or 75 minutes per week of vigorous-intensity physical activity ^c206
  • For adults with type 2 diabetes mellitus, making lifestyle changes and meeting exercise recommendations are crucial. Metformin is first line therapy, followed by consideration of a sodium-glucose cotransporter 2 inhibitor or a glucagon-like peptide-1 receptor agonist
  • Advise patients to stop smoking, if necessary. Refer active smokers to counseling in combination with drug therapy (using nicotine replacement, bupropion, or varenicline) ^c207d12
  • Advise patients that aspirin should be used infrequently in routine primary prevention of atherosclerotic cardiovascular disease owing to lack of net benefit ^r101
  • Statin therapy is first line treatment for primary prevention of atherosclerotic cardiovascular disease in patients with:
    • Elevated LDL-C levels (190 mg/dL or higher)
    • Diabetes mellitus (patients aged 40-75 years)
    • Sufficient atherosclerotic cardiovascular disease risk (determined by clinician-patient risk discussion)
  • Nonpharmacologic interventions are recommended for all adults with elevated blood pressure or hypertension. For those requiring pharmacologic therapy, target blood pressure is generally lower than 130/80 mm Hg
• Surgical procedures to improve carotid artery blood flow may be indicated in patients with carotid artery stenosis, and include: ^r98
  • CEA (carotid endarterectomy)
  • Carotid artery angioplasty
  • Stenting
  • European guidelines recommend carotid endarterectomy in patients with 60% or greater asymptomatic carotid artery stenosis who are considered to be at increased risk of stroke despite best medical therapy ^r6