Ischemic stroke medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S [2]

Overview

The medical therapy of ischemic stroke is mainly directed to fibrinolysis of clot by r-tPA with in 3 to 4.5 hours of symptom onset. Acute treatment with antiplatelets may have a role if given within 24-48 hours of stroke onset. Long term management with statins, antiplatelets, anticoagulants, antihypertensive and antidiabetic agents may help prevent the recurrence.^[1] Acute treatment to control blood pressure, blood glucose and fever may help prevent the complications and have a prognostic significance.

Medical Therapy

The reported cases of treatment for COVID-19-associated stroke have followed the same guidelines as patients with no COVID-19 infection. The following recommendations are mainly based on the current guidelines of management for stroke of the AHA 2019.
IV alteplase is always preferred over mechanical thrombectomy when there are no contraindications.^[2]
The usefulness of anticoagulants such as thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) is not well established in the acute setting of stroke.^[3]
The use of thrombolysis via ultrasound waves concomitant to IV fibrinolysis is not recommended.^[4]
High-intensity statin therapy should be initiated in patients younger than 75 with clinical ASCVD, to achieving a reduction in LDL-C levels of at least 50%.
In patients older than 75 years of age with clinical ASCVD, it is reasonable to initiate moderate or high-intensity statin therapy after reviewing adverse effects and drug interactions.^[5]^[6]
Risk and beneffits should be discussed before initiation of statin therapy to weight ASCVD risk reduction against the potential for statin-associated side effects.^[5]
Continuation of statin therapy during the acute period of ischemic stroke is reasonable among patients already taking statins.

Alteplase

IV alteplase is recommended for selected patients who can be treated within 3-4.5 hours of ischemic stroke symptom onset or patient last known well or at baseline state.^[7]^[5]^[8]
The dose of IV alteplase is 0.9 mg/kg (maximum dose 90 mg) over 60 min, with 10% of the dose given as a bolus over 1 min.^[5]
IV alteplase should be initiated as soon as possible, having been demonstrated better outcomes the sooner is administered.^[5]
Hyperglycemia should be treated during the first 24 hours after ischemic stroke, to achieve values of 140 to 180 mg/dL.^[5]
IV alteplase may cause bleeding and angioedema.^[5]
Glycoprotein IIb/IIIa inhibitors (tirofiban, apiximab, eptifibatide) should not be coadministered with IV alteplase.^[5]^[9]
IV alteplase may be used in patients under warfarin if the INR is lower than 1.7.^[5]
IV alteplase should not be administered to patients who have received a full dose of low-molecular-weight heparin within the previous 24 hours (including prophylactic doses).^[5]^[10]
Blood pressure should be sustained lower than 180/105 mmHg the first 24 hours after IV alteplase administration. Intensive lowering has been shown to be safe.^[5]^[11]
In case of intracranial bleeding due to alteplase administration, alteplase should be suspended, blood draws should be taken (CBC, coagulation studies), tranexamic acid should be administered (1000 mg IV infused over 10 min), and a subsecuent non-contratested CT scan of the head taken.^[12]
The use of IV alteplase should be used cautiously in patients who undergone a major surgery in the past 2 weeks.^[5]
IV alteplase for ischemic stroke is contraindicated in patients with a severe head trauma or subarachnoid hemorrage in the preceding 3 months.^[5]

Tenecteplase

Tenecteplase may be useful in patients with minor neurological impairment.^[13]
The dose of tenecteplase is a single IV bolus of 0.25-mg/kg (maximum 25 mg).^[14]

Antiplatelet therapy

Administration of aspirin is recommended in patients with AIS within 24 to 48 hours after onset. For those treated with IV alteplase, aspirin administration is generally delayed until 24 hours later.^[15]
The dose of aspirin is usually between 160-300mg daily.^[16]
IV aspirin administration within 90 minutes after the start of IV alteplase is associated with symptomatic intracranial hemorrhage, for which co administration is discouraged but benefits should be assessed in each individual case.^[5]^[17]
Dual antiplatelet therapy with aspirin and clopidogrel (75 mg/d, with a loading dose of 600mg) may be started within 24 hours after symptom onset and continued for 21 days in patients with no cardioembolic ischemic stroke.^[18]
Aspirin should not substitute IV alteplase or mechanical thrombectomy in patients eligible for these therapies.^[5]


Medical treatment	Drug class	Recommendations
Medical treatment	Drug class	Acute	Long-Term
Reperfusion therapy	Tissue plasminogen activator (t-PA)	Recommended within 3-4.5 hours of onset of ischemic stroke in eligible patients by guidelines^[19]^[20]^[21] and systematic reviews^[22]^[23]^[24]	None
Antithrombotic agents	Antiplatelet agents	Oral administration of aspirin (initial dose is 325 mg) is recommended within 24 to 48 hours after stroke onset in most patients^[19] Aspirin is contraindicated in patients with ischemic stroke within 24 hours of t-PA administration^[19] DAPT therapy (aspirin and clopidogrel) is recommended for 90 days in patients with symptomatic intracranial large artery disease	Long term therapy with clopidogrel or aspirin extended release dipyridamole may be used for secondary prevention of non cardioembolic stroke
Antithrombotic agents	Anticoagulants	Parenteral or oral anticoagulation is not recommended within 48 hours of onset of ischemic stroke^[25]	Oral anticoagulants may be used for secondary prevention of ischemic stroke in patients with atrial fibrillation or other cardioembolic disease^[26]
Antilipid therapy	Statins	Among patients already taking statins at the time of onset of ischemic stroke, continuation of statin therapy during the acute period is reasonable^[19]	Long term management of ischemic stroke with high intensity statins may be recommended for patients with atherosclerotic disease Patients who cannot tolerate high intensity dose, medium or low intensity statins may prove beneficial
Antihypertensive therapy	Intravenous antihypertensives (Labetolol, nitroprusside)	Used to control high blood pressure in patients with BP>185/110 mmHg before starting t-PA^[19]	Long term oral antihypertensives may be used after 24 hours of ischemic stroke in patients having history of hypertension
Antihypertensive therapy	Oral antihypertensive therapy	Recommended after 24 hours in patient having hypertension	Long term oral antihypertensives may be used after 24 hours of ischemic stroke in patients having history of hypertension
Antihyperglycemic agents	Insulin	May be used to control blood glucose between range of 140-180 mg/dl since hyperglycemia is associated with worst outcome in patients with acute ischemic stroke^[19]	Long term oral antidiabetic may be used for secondary prevention of ischmeic stroke in patients with diabetes mellitus

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^[27]

IV Alteplase Eligibility

Class I
1. Administration of IV alteplase in eligible patients without first obtaining MRI to exclude cerebral microbleeds (CMBs) is recommended(Level of Evidence: B-NR)
2.In patients eligible for IV alteplase, because benefit of therapy is time dependent, treatment should be initiated as quickly as possible and not delayed for additional multimodal neuroimaging, such as CT and MRI perfusion imaging.(Level of Evidence: B-NR)

Class IIa
1. In patients with AIS who awake with stroke symptoms or have unclear time of onset > 4.5 hours from last known well or at baseline state, MRI to identify diffusion-positive FLAIR-negative lesions can be useful for selecting those who can benefit from IV alteplase administration within 4.5 hours of stroke symptom recognition.(Level of Evidence: B-R)

2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association^[28]

Recommendations for Intracranial Large Artery Atherosclerosis Referenced studies that support recommendations are summarized in online Data Supplements 20-27

Antithrombotic therapy

Class I
1. In patients with a stroke or TIA caused by 50% to 99% stenosis of a major intracranial artery, aspirin 325 mg/d is recommended in preference to warfarin to reduce the risk of recurrent ischemic stroke and vascular death.(Level of Evidence: B-R)

Class IIa
2. In patients with recent stroke or TIA (within 30 days) attributable to severe stenosis (70%–99%) of a major intracranial artery, the addition of clopidogrel 75 mg/d to aspirin for up to 90 days is reasonable to further reduce recurrent stroke risk(Level of Evidence: B-NR)

Class IIb
3. In patients with recent (within 24 hours) minor stroke or high-risk TIA and concomitant ipsilateral >30% stenosis of a major intracranial artery, the addition of ticagrelor 90 mg twice a day to aspirin for up to 30 days might be considered to further reduce recurrent stroke risk.(Level of Evidence: B-NR) 4. In patients with stroke or TIA attributable to 50% to 99% stenosis of a major intracranial artery, the addition of cilostazol 200 mg/day to aspirin or clopidogrel might be considered to reduce recurrent stroke risk(Level of Evidence: C-LD) 5. In patients with stroke or TIA attributable to 50% to 99% stenosis of a major intracranial artery, the usefulness of clopidogrel alone, the combination of aspirin and dipyridamole, ticagrelor alone, or cilostazol alone for secondary stroke prevention is not well established.(Level of Evidence: C-EO)

Risk Factor Management

Class I
6. In patients with a stroke or TIA attributable to 50% to 99% stenosis of a major intracranial artery, maintenance of SBP below 140 mm Hg, high-intensity statin therapy, and at least moderate physical activity are recommended to prevent recurrent stroke and vascular events.(Level of Evidence: B-NR)

Angioplasty and Stenting

Class IIb
7. In patients with severe stenosis (70%-99%) of a major intracranial artery and actively progressing symptoms or recurrent TIA or stroke after institution of aspirin and clopidogrel therapy, achievement of SBP <140 mm Hg, and high- intensity statin therapy (so-called medical failures), the usefulness of angioplasty alone or stent placement to prevent ischemic stroke in the territory of the stenotic artery is unknown.(Level of Evidence: C-LD)

Recommendations for Extracranial Carotid Stenosis Referenced studies that support recommendations are summarized in online Data Supplement 28

Class I
3. In patients with carotid artery stenosis and a TIA or stroke, intensive medical therapy, with antiplatelet therapy, lipid-lowering therapy, and treatment of hypertension, is recommended to reduce stroke risk(Level of Evidence: A)

Recommendations for Extracranial Vertebral Artery Stenosis Referenced studies that support recommendations are summarized in online Data Supplement 28

Class I
1. In patients with recently symptomatic extracranial vertebral artery stenosis, intensive medical therapy (antiplatelet therapy, lipid lowering, BP control) is recommended to reduce stroke risk.(Level of Evidence: A)

Recommendations for Aortic Arch Atherosclerosis Referenced studies that support recommendations are summarized in online Data Supplement 29

Class I
1. In patients with a stroke or TIA and evidence of an aortic arch atheroma, intensive lipid management to an LDL cholesterol target <70 mg/dL is recommended to prevent recur-rent stroke(Level of Evidence: B-R) 2. In patients with a stroke or TIA and evidence of an aortic arch atheroma, antiplatelet therapy is recommended to prevent recurrent stroke.(Level of Evidence: C-LD)

Recommendations for Moyamoya Disease Referenced studies that support recommendations are summarized in online Data Supplement 30

Class IIa
1. In patients with moyamoya disease and a history of ischemic stroke or TIA, surgical revascularization with direct or indirect extracranial-intracranial bypass can be beneficial for the prevention of ischemic stroke or TIA(Level of Evidence: C-LD)

Class IIb
2. In patients with moyamoya disease and a history of ischemic stroke or TIA, the use of anti-platelet therapy, typically aspirin monotherapy, for the prevention of ischemic stroke or TIA may be reasonable.(Level of Evidence: C-LD)

Recommendation for Small Vessel Stroke Referenced studies that support the recommendation are summarized in online Data Supplement 31

Class IIb
1.In patients with ischemic stroke related to small vessel disease, the usefulness of cilostazol for secondary stroke prevention is uncertain(Level of Evidence: B-R)

For AHA/ASA guidelines for Intravenous Fibrinolysis in patients with ischemic stroke, please click here
For AHA/ASA guidelines for General Supportive Care and Treatment of Acute Complications in patients with ischemic stroke, please click here
For AHA/ASA guidelines on anticoagulants usage in patients with ischemic stroke, please click here
For AHA/ASA guidelines on antiplatelets usage in patients with ischemic stroke, please click here
For AHA/ASA guidelines on volume resuscitation usage in patients with ischemic stroke, please click here
For AHA/ASA guidelines on neuroprotective agents in patients with ischemic stroke, please click here
For AHA/ASA guidelines on General Stroke Care in patients with ischemic stroke, please click here

References

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