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

Tenecteplase

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
Acute Long-Term
Reperfusion therapy Tissue plasminogen activator (t-PA)
  • 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
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
Oral antihypertensive therapy
  • 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)

IV Alteplase - General Priniciples

Class I
1. In patients eligible for IV alteplase, benefit of therapy is time dependent, and treatment should be initiated as quickly as possible. (Level of Evidence: A)
2. In patients undergoing fibrinolytic therapy, physicians should be prepared to treat potential emergent adverse effects, including bleeding complications and angioedema that may cause partial airway obstruction. (Level of Evidence: B-NR)
3. The potential risks should be discussed during IV alteplase eligibility deliberation and weighed against the anticipated benefits during decision- making.Level of Evidence: C-EO)

Time Windows

Class I
1. IV alteplase (0.9 mg/kg, maximum dose 90 mg over 60 minutes with initial 10% of dose given as bolus over 1 minute) is recommended for selected patients who can be treated within 3 hours of ischemic stroke symptom onset or patient last known well or at baseline state. Physicians should review the criteria outlined in Table 8 to determine patient eligibility.(Level of Evidence: A)
2. IV alteplase (0.9 mg/kg, maximum dose 90 mg over 60 minutes with initial 10% of dose given as bolus over 1 minute) is also recommended for selected patients who can be treated within 3 and 4.5 hours of ischemic stroke symptom onset or patient last known well or at baseline state. Physicians should review the criteria outlined in Table 8 to determine patient eligibility. (Level of Evidence: B-R)
Class IIa
1.IV alteplase (0.9 mg/kg, maximum dose 90 mg over 60 minutes with initial 10% of dose given as bolus over 1 minute) administered within 4.5 hours of stroke symptom recognition can be beneficial 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 and who have a DW-MRI lesion smaller than one-third of the MCA territory and no visible signal change on FLAIR. (Level of Evidence: B-R)

Antiplatelet Treatment

Class I
1. 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 but might be considered in the presence of concomitant conditions for which such treatment given in the absence of IV alteplase is known to provide substantial benefit or withholding such treatment is known to cause substantial risk.(Level of Evidence: A)
2. In patients presenting with minor noncardioembolic ischemic stroke (NIHSS score ≤3) who did not receive IV alteplase, treatment with dual antiplatelet therapy (aspirin and clopidogrel) started within 24 hours after symptom onset and continued for 21 days is effective in reducing recurrent ischemic stroke for a period of up to 90 days from symptom onset. (Level of Evidence: A)
Class IIa
1.The efficacy of the IV glycoprotein IIb/IIIa inhibitors tirofiban and eptifibatide in the treatment of AIS is not well established.(Level of Evidence: B-R)

Anticoagulants

Class IIa
1. The usefulness of urgent anticoagulation in patients with severe stenosis of an internal carotid artery ipsilateral to an ischemic stroke is not well established.(Level of Evidence: B-R)
2. The safety and usefulness of short-term anticoagulation for nonocclusive, extracranial intraluminal thrombus in the setting of AIS are not well established.. (Level of Evidence: C-LD)
3. At present, the usefulness of argatroban, dabigatran, or other thrombin inhibitors for the treatment of patients with AIS is not well established.  (Level of Evidence: B-R)
4. The safety and usefulness of oral factor Xa inhibitors in the treatment of AIS are not well established.(Level of Evidence: C-LD)

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)

Recommendations for AF Referenced studies that support recommendations are summarized in online Data Supplement 32

Class I
1.     In patients with nonvalvular AF and stroke or TIA, oral anticoagulation (eg, apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin) is recommended to reduce the risk of recurrent stroke.(Level of Evidence: A)

2.     In patients with AF and stroke or TIA, oral anticoagulation is indicated to reduce the risk of recurrent stroke regardless of whether the AF pattern is paroxysmal, persistent, or permanent.(Level of Evidence: B-R) 3.     In patients with stroke or TIA and AF who do not have moderate to severe mitral stenosis or a mechanical heart valve, apixaban, dabigatran, edoxaban, or rivaroxaban is recommended in preference to warfarin to reduce the risk of recurrent stroke.(Level of Evidence: B-R) 4.     In patients with atrial flutter and stroke or TIA, anticoagulant therapy similar to that in AF is indicated to reduce the risk of recurrent stroke.(Level of Evidence: B-NR) 5.     In patients with AF and stroke or TIA, without moderate to severe mitral stenosis or a mechanical heart valve, who are unable to maintain a therapeutic INR level with warfarin, use of dabigatran, rivaroxaban, apixaban, or edoxaban is recommended to reduce the risk of recurrent stroke.(Level of Evidence: C-EO)

Class IIa
6.     In patients with stroke at high risk of hemorrhagic conversion in the setting of AF, it is reasonable to delay initiation of oral anticoagulation beyond 14 days to reduce the risk of ICH.(Level of Evidence: B-NR)

7.    In patients with TIA in the setting of nonvalvular AF, it is reasonable to initiate anticoagulation immediately after the index event to reduce the risk of recurrent stroke.(Level of Evidence: C-EO)

Class IIb
8.     In patients with stroke or TIA in the setting of nonvalvular AF who have contraindications for lifelong anticoagulation but can tolerate at least 45 days, it may be reasonable to consider percutaneous closure of the left atrial appendage with the Watchman device to reduce the chance of recurrent stroke and bleeding.(Level of Evidence: B-R)

9.     In patients with stroke at low risk for hemorrhagic conversion in the setting of AF, it may be reasonable to initiate anticoagulation 2 to 14 days after the index event to reduce the risk of recurrent stroke.(Level of Evidence: B-NR) 10.  In patients with AF and stroke or TIA who have end-stage renal disease or are on dialysis, it may be reasonable to use warfarin or apixaban (dose adjusted if indicated) for anticoagulation to reduce the chance of recurrent stroke. (Level of Evidence: B-NR)

Recommendations for Valvular Disease Referenced studies that support recommendations are summarized in online Data Supplement 33 and 34

Class I
1.     In patients with ischemic stroke or TIA and valvular AF (moderate to severe mitral steno-sis or any mechanical heart valve), warfarin is recommended to reduce the risk of recurrent stroke or TIA.(Level of Evidence: B-R)

2.     In patients with a mechanical mitral valve and a history of ischemic stroke or TIA before valve replacement, aspirin (75–100 mg/d) is recommended in addition to warfarin with an INR target of 3.0 (range, 2.5–3.5) to reduce the risk of thrombosis and recurrent stroke or TIA.(Level of Evidence: C-LD) 3.     In patients with ischemic stroke or TIA and native aortic or nonrheumatic mitral valve disease (eg, mitral annular calcification or mitral valve prolapse) who do not have AF or another indication for anticoagulation, anti-platelet therapy is recommended to reduce the risk of recurrent stroke or TIA.(Level of Evidence: C-EO) 4.     In patients with a bioprosthetic aortic or mitral valve, a history of ischemic stroke or TIA before valve replacement, and no other indication for anticoagulation therapy beyond 3 to 6 months from the valve placement, long-term therapy with aspirin is recommended in preference to long-term anticoagulation to reduce the risk of recur-rent stroke or TIA.(Level of Evidence: C-EO)

Class IIa
6.     In patients with history of ischemic stroke or TIA and a mechanical aortic valve, anti-coagulation with higher-intensity warfarin to achieve an INR of 3.0 (range, 2.5–3.5) or the addition of aspirin (75–100 mg/d) can be beneficial to reduce the risk of thromboembolic events(Level of Evidence: C-EO)

Recommendations for LV Thrombus Referenced studies that support recommendations are summarized in online Data Supplement 35

Class I
1.     In patients with stroke or TIA and LV thrombus, anticoagulation with therapeutic warfarin for at least 3 months is recommended to reduce the risk of recurrent stroke.(Level of Evidence: B-NR)
Class IIb
3.     In patients with stroke or TIA and new LV thrombus (<3 months), the safety of anticoagulation with a direct oral anticoagulant to reduce risk of recurrent stroke is uncertain.(Level of Evidence: C-LD)

4.     In patients with stroke or TIA in the setting of acute anterior MI with reduced ejection fraction (EF; <50%) but no evidence of LV thrombus, empirical anticoagulation for at least 3 months might be considered to reduce the risk of recurrent cardioembolic stroke.(Level of Evidence: C-EO)

Recommendations for Cardiomyopathy Referenced studies that support recommendations are summarized in online Data Supplements 36 and 37

Class I
1.     In patients with ischemic stroke or TIA and left atrial or left atrial appendage thrombus in the setting of ischemic, nonischemic, or restrictive cardiomyopathy and LV dysfunction, anticoagulant therapy with warfarin is recommended for at least 3 months to reduce the risk of recurrent stroke or TIA. (Level of Evidence: C-EO)
Class IIa
2. In patients with ischemic stroke or TIA in the setting of a mechanical assist device, treatment with warfarin and aspirin can be beneficial to reduce the risk of recurrent stroke or TIA.(Level of Evidence: C-LD)

3. In patients with ischemic stroke or TIA in the setting of LV noncompaction, treatment with warfarin can be beneficial to reduce the risk of recurrent stroke or TIA. (Level of Evidence: C-EO)

Class IIb
4.     In patients with ischemic stroke or TIA in sinus rhythm with ischemic or nonischemic cardio-myopathy and reduced EF without evidence of left atrial or LV thrombus, the effectiveness of anticoagulation compared with antiplatelet therapy is uncertain, and the choice should be individualized.(Level of Evidence: B-R)

Recommendations for Congenital Heart Disease Referenced studies that support recommendations are summarized in online Data Supplements 40 and 41

Class I
1. In patients with ischemic stroke or TIA and Fontan palliation, anticoagulation with warfarin is recommended to reduce the risk of recurrent stroke or TIA.(Level of Evidence: C-LD)
Class IIa
2.   In patients with cyanotic congenital heart disease and other complex lesions, ischemic stroke or TIA of presumed cardioembolic origin, therapy with warfarin is reasonable to reduce the risk of recurrent stroke or TIA(Level of Evidence: C-EO)

Recommendations for Dissection Referenced studies that support recommendations are summarized in online Data Supplements 43 and 44

Class I
1.  In patients with ischemic stroke or TIA after an extracranial carotid or vertebral arterial dis-section, treatment with antithrombotic therapy for at least 3 months is indicated to prevent recurrent stroke or TIA.(Level of Evidence: C-EO)
Class IIa
2. In patients with ischemic stroke or TIA who are <3 months after an extracranial carotid or vertebral arterial dissection, it is reasonable to use either aspirin or warfarin to prevent recur-rent stroke or TIA.(Level of Evidence: B-R)
Class IIb
3.     In patients with stroke or TIA and extracranial carotid or vertebral artery dissection who have recurrent events despite antithrombotic therapy, endovascular therapy may be considered to prevent recurrent stroke or TIA.(Level of Evidence: C-LD)

Recommendation for Hematologic Traits Referenced studies that support the recommendation are summarized in online Data Supplement 45

Class IIa
1.     In patients with ischemic stroke or TIA of unknown source despite thorough diagnostic evaluation and no other thrombotic history who are found to have prothrombin 20210A mutation, activated protein C resistance, elevated factor VIII levels, or deficiencies of protein C, protein S, or antithrombin III, anti-platelet therapy is reasonable to reduce the risk of recurrent stroke or TIA (Level of Evidence: C-LD)

Recommendations for Antiphospholipid Syndrome Referenced studies that support recommendations are summarized in online Data Supplement 46

Class I
1.     In patients with ischemic stroke or TIA who have an isolated antiphospholipid antibody but do not fulfill the criteria for antiphospholipid syndrome, antiplatelet therapy alone is recommended to reduce the risk of recurrent stroke. (Level of Evidence: B-NR)
Class IIa
2.     In patients with ischemic stroke or TIA with confirmed antiphospholipid syndrome treated with warfarin, it is reasonable to choose a target INR between 2 and 3 over a target INR >3 to effectively balance the risk of excessive bleeding against the risk of thrombosis.(Level of Evidence: B-R)

3.     In patients with ischemic stroke or TIA who meet the criteria for the antiphospholipid syndrome, it is reasonable to anticoagulate with warfarin to reduce the risk of recurrent stroke or TIA.(Level of Evidence: C-LD)

Recommendation for Malignancy Referenced studies that support the recommendation are summarized in online Data Supplement 48

Class IIa
1.  In patients with ischemic stroke or TIA in the setting of AF and cancer, it is reasonable to consider anticoagulation with DOACs in preference to warfarin for stroke prevention (Level of Evidence: B-NR)

Recommendations for Sickle Cell Disease Referenced studies that support recommendations are summarized in online Data Supplement 49

Class I
1.   In patients with sickle cell disease (SCD) and prior ischemic stroke or TIA, chronic blood transfusion(s) to reduce hemoglobin S to <30% of total hemoglobin is recommended for the prevention of recurrent ischemic stroke.(Level of Evidence: B-NR)
Class IIa
2.     In patients with SCD with prior ischemic stroke or TIA for whom transfusion therapy is not available or practical, treatment with hydroxyurea is reasonable for the prevention of recurrent ischemic stroke.(Level of Evidence: B-R)

Recommendations for Autoimmune Vasculitis Referenced studies that support recommendations are summarized in online Data Supplement 50

Class I
1.In patients with ischemic stroke or TIA and symptoms attributed to giant cell arteritis, immediate initiation of oral high-dose glucocorticoids is recommended to reduce recurrent stroke risk(Level of Evidence: B-NR)
Class IIa
2. In patients with ischemic stroke or TIA and diagnosis of giant cell arteritis, methotrexate or tocilizumab therapy adjunctive to steroids is reasonable to lower the risk of recurrent stroke.(Level of Evidence: B-NR)

3. In patients with ischemic stroke or TIA and diagnosis of primary CNS angiitis, induction therapy with glucocorticoids and/or immunosuppressants followed by long-term maintenance therapy with steroid-sparing immunosuppressants is reasonable to lower the risk of stroke recurrence.(Level of Evidence: B-NR)

Recommendations for Infectious Vasculitis Referenced studies that support recommendations are summarized in online Data Supplement 51

Class I
1. In patients with ischemic stroke or TIA and infectious vasculitis such as varicella zoster virus (VZV) cerebral vasculitis, neurosyphilis, or bacterial meningitis, treating the underlying infectious etiology is indicated to reduce the risk of stroke.(Level of Evidence: B-NR)
Class IIa
2. In patients with ischemic stroke or TIA in the context of HIV vasculopathy, daily aspirin plus HIV viral control with combined antiretroviral therapy is reasonable to reduce the risk of recurrent stroke(Level of Evidence: C-LD)

Recommendations for Other Genetic Disorders Referenced studies that support recommendations are summarized in online Data Supplements 51 and 52

Class I
1.  In patients with ischemic stroke or TIA and cystathionine β-synthase deficiency, pyridoxine (in responsive patients) and a low-methionine, cysteine-enhanced diet supplemented with pyridoxine, vitamin B12, and folate are recommended to reduce plasma homocysteine to population normal levels and thereby reduce the risk of recurrent ischemic stroke.(Level of Evidence: C-LD)
Class IIb
2.  In patients with ischemic stroke or TIA and Anderson-Fabry disease, agalsidase alfa or agalsidase beta is of uncertain value in preventing recurrent stroke or TIA (Level of Evidence: B-NR)

Recommendations for Carotid Web Referenced studies that support recommendations are summarized in online Data Supplement 53

Class I
1.     In patients with carotid web in the distribution of ischemic stroke and TIA, without other attributable causes of stroke, antiplatelet therapy is recommended to prevent recurrent ischemic stroke or TIA.(Level of Evidence: B-NR)
Class IIb
2.     In patients with carotid web in the distribution of ischemic stroke refractory to medical management, with no other attributable cause of stroke despite comprehensive workup, carotid stenting or CEA may be considered to prevent recurrent ischemic stroke. (Level of Evidence: C-LD)

Recommendations for Fibromuscular Dysplasia Referenced studies that support recommendations are summarized in online Data Supplement 54

Class I
1.     In patients with fibromuscular dysplasia (FMD) and a history of ischemic stroke or TIA without other attributable causes, antiplatelet therapy, BP control, and lifestyle modification are recommended for the prevention of future ischemic events.(Level of Evidence: C-LD)
Class IIa
2.   In patients with a history of ischemic stroke or TIA attributable to dissection, with FMD, and no evidence of intraluminal thrombus, it is reasonable to administer antiplatelet therapy for the prevention of future ischemic events.(Level of Evidence: C-EO)
Class IIb
3.     In patients with cervical carotid artery FMD and recurrent ischemic stroke without other attributable causes despite optimal medical management, carotid angioplasty with or without stenting may be reasonable to prevent ischemic stroke.(Level of Evidence: C-LD)

Recommendation for Dolichoectasia Referenced studies that support the recommendation are summarized in online Data Supplement 55

Class IIa
1.In patients with vertebrobasilar dolichoectasia and a history of ischemic stroke or TIA without other attributable causes, the use of antiplatelet or anticoagulant therapy is reasonable for the prevention of recurrent ischemic events.(Level of Evidence: C-LD)

Recommendations for Antithrombotic Medications Referenced studies that support recommendations are summarized in online Data Supplement 57-59

Class I
1.     In patients with non-cardioembolic ischemic stroke or TIA, antiplatelet therapy is indicated in preference to oral anticoagulation to reduce the risk of recurrent ischemic stroke and other cardiovascular events while minimizing the risk of bleeding.(Level of Evidence: A)

2.     For patients with non-cardioembolic ischemic stroke or TIA, aspirin 50 to 325 mg daily, clopidogrel 75 mg, or the combination of aspirin 25 mg and extended-release dipyridamole 200 mg twice daily is indicated for secondary prevention of ischemic stroke.(Level of Evidence: A) 3.   For patients with recent minor (NIHSS score ≤3) non-cardioembolic ischemic stroke or high-risk TIA (ABCD2 score ≥4), DAPT (aspirin plus clopidogrel) should be initiated early (ideally within 12–24 hours of symptom onset and at least within 7 days of onset) and continued for 21 to 90 days, followed by SAPT, to reduce the risk of recurrent ischemic stroke.(Level of Evidence: A)

Class IIb
4. For patients with recent (< 24 hours) minor to moderate stroke (NIHSS score ≤5), high-risk TIA (ABCD2 score ≥6), or symptomatic intra-cranial or extracranial ≥30% stenosis of an artery that could account for the event, DAPT with ticagrelor plus aspirin for 30 days may be considered to reduce the risk of 30-day recurrent stroke but may also increase the risk of serious bleeding events, including ICH.(Level of Evidence: B-R)

5. For patients already taking aspirin at the time of non-cardioembolic ischemic stroke or TIA, the effectiveness of increasing the dose of aspirin or changing to another antiplatelet medication is not well established.(Level of Evidence: B-NR )




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

  1. ↑ Hackam DG, Spence JD (2007). "Combining multiple approaches for the secondary prevention of vascular events after stroke: a quantitative modeling study". Stroke. 38 (6): 1881–5. doi:10.1161/STROKEAHA.106.475525. PMID 17431209.
  2. ↑ Saver, Jeffrey L.; Goyal, Mayank; van der Lugt, Aad; Menon, Bijoy K.; Majoie, Charles B. L. M.; Dippel, Diederik W.; Campbell, Bruce C.; Nogueira, Raul G.; Demchuk, Andrew M.; Tomasello, Alejandro; Cardona, Pere; Devlin, Thomas G.; Frei, Donald F.; du Mesnil de Rochemont, Richard; Berkhemer, Olvert A.; Jovin, Tudor G.; Siddiqui, Adnan H.; van Zwam, Wim H.; Davis, Stephen M.; Castaño, Carlos; Sapkota, Biggya L.; Fransen, Puck S.; Molina, Carlos; van Oostenbrugge, Robert J.; Chamorro, Ángel; Lingsma, Hester; Silver, Frank L.; Donnan, Geoffrey A.; Shuaib, Ashfaq; Brown, Scott; Stouch, Bruce; Mitchell, Peter J.; Davalos, Antoni; Roos, Yvo B. W. E. M.; Hill, Michael D. (2016). "Time to Treatment With Endovascular Thrombectomy and Outcomes From Ischemic Stroke: A Meta-analysis". JAMA. 316 (12): 1279. doi:10.1001/jama.2016.13647. ISSN 0098-7484.
  3. ↑ Gioia, Laura C.; Kate, Mahesh; Sivakumar, Leka; Hussain, Dulara; Kalashyan, Hayrapet; Buck, Brian; Bussiere, Miguel; Jeerakathil, Thomas; Shuaib, Ashfaq; Emery, Derek; Butcher, Ken (2016). "Early Rivaroxaban Use After Cardioembolic Stroke May Not Result in Hemorrhagic Transformation". Stroke. 47 (7): 1917–1919. doi:10.1161/STROKEAHA.116.013491. ISSN 0039-2499.
  4. ↑ Nacu, Aliona; Kvistad, Christopher E.; Naess, Halvor; Øygarden, Halvor; Logallo, Nicola; Assmus, Jörg; Waje-Andreassen, Ulrike; Kurz, Kathinka D.; Neckelmann, Gesche; Thomassen, Lars (2017). "NOR-SASS (Norwegian Sonothrombolysis in Acute Stroke Study)". Stroke. 48 (2): 335–341. doi:10.1161/STROKEAHA.116.014644. ISSN 0039-2499.
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 5.13 5.14 Powers, William J.; Rabinstein, Alejandro A.; Ackerson, Teri; Adeoye, Opeolu M.; Bambakidis, Nicholas C.; Becker, Kyra; Biller, José; Brown, Michael; Demaerschalk, Bart M.; Hoh, Brian; Jauch, Edward C.; Kidwell, Chelsea S.; Leslie-Mazwi, Thabele M.; Ovbiagele, Bruce; Scott, Phillip A.; Sheth, Kevin N.; Southerland, Andrew M.; Summers, Deborah V.; Tirschwell, David L. (2019). "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). doi:10.1161/STR.0000000000000211. ISSN 0039-2499.
  6. ↑ Sanossian, Nerses; Saver, Jeffrey L.; Liebeskind, David S.; Kim, Doojin; Razinia, Tannaz; Ovbiagele, Bruce (2006). "Achieving Target Cholesterol Goals After Stroke". Archives of Neurology. 63 (8): 1081. doi:10.1001/archneur.63.8.1081. ISSN 0003-9942.
  7. ↑ Lees, Kennedy R.; Emberson, Jonathan; Blackwell, Lisa; Bluhmki, Erich; Davis, Stephen M.; Donnan, Geoffrey A.; Grotta, James C.; Kaste, Markku; von Kummer, Rüdiger; Lansberg, Maarten G.; Lindley, Richard I.; Lyden, Patrick; Murray, Gordon D.; Sandercock, Peter A.G.; Toni, Danilo; Toyoda, Kazunori; Wardlaw, Joanna M.; Whiteley, William N.; Baigent, Colin; Hacke, Werner; Howard, George; Marler, John; Halls, Heather; Holland, Lisa; Mathews, Clare; Smith, Samantha; Wilson, Kate; Koga, Masatoshi; Albers, Gregory; Brott, Thomas; Cohen, Geoffrey; Koga, Masatoshi; Olivot, Jean Marc; Parsons, Mark; Tilley, Barbara; Wahlgren, Nils; del Zoppo, Gregory J (2016). "Effects of Alteplase for Acute Stroke on the Distribution of Functional Outcomes". Stroke. 47 (9): 2373–2379. doi:10.1161/STROKEAHA.116.013644. ISSN 0039-2499.
  8. ↑ "The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial". The Lancet. 379 (9834): 2352–2363. 2012. doi:10.1016/S0140-6736(12)60768-5. ISSN 0140-6736.
  9. ↑ Adeoye, Opeolu; Sucharew, Heidi; Khoury, Jane; Tomsick, Thomas; Khatri, Pooja; Palesch, Yuko; Schmit, Pamela A.; Pancioli, Arthur M.; Broderick, Joseph P. (2015). "Recombinant Tissue-Type Plasminogen Activator Plus Eptifibatide Versus Recombinant Tissue-Type Plasminogen Activator Alone in Acute Ischemic Stroke". Stroke. 46 (2): 461–464. doi:10.1161/STROKEAHA.114.006743. ISSN 0039-2499.
  10. ↑ Powers, William J.; Derdeyn, Colin P.; Biller, José; Coffey, Christopher S.; Hoh, Brian L.; Jauch, Edward C.; Johnston, Karen C.; Johnston, S. Claiborne; Khalessi, Alexander A.; Kidwell, Chelsea S.; Meschia, James F.; Ovbiagele, Bruce; Yavagal, Dileep R. (2015). "2015 American Heart Association/American Stroke Association Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment". Stroke. 46 (10): 3020–3035. doi:10.1161/STR.0000000000000074. ISSN 0039-2499.
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  12. ↑ Sloan, M. A.; Price, T.R.; Petito, C. K.; Randall, A. M. Y.; Solomon, R. E.; Terrin, M. L.; Gore, J.; Collen, D.; Kleiman, N.; Feit, F.; Babb, J.; Herman, M.; Roberts, W. C.; Sopko, G.; Bovill, E.; Forman, S.; Knatterud, G. L. (1995). "Clinical features and pathogenesis of intracerebral hemorrhage after rt-PA and heparin therapy for acute myocardial infarction: The Thrombolysis in Myocardial Infarction (TIMI) II Pilot and Randomized Clinical Trial Combined experience". Neurology. 45 (4): 649–658. doi:10.1212/WNL.45.4.649. ISSN 0028-3878.
  13. ↑ Huang, Xuya; Cheripelli, Bharath Kumar; Lloyd, Suzanne M; Kalladka, Dheeraj; Moreton, Fiona Catherine; Siddiqui, Aslam; Ford, Ian; Muir, Keith W (2015). "Alteplase versus tenecteplase for thrombolysis after ischaemic stroke (ATTEST): a phase 2, randomised, open-label, blinded endpoint study". The Lancet Neurology. 14 (4): 368–376. doi:10.1016/S1474-4422(15)70017-7. ISSN 1474-4422.
  14. ↑ Campbell, Bruce C.V.; Mitchell, Peter J.; Churilov, Leonid; Yassi, Nawaf; Kleinig, Timothy J.; Dowling, Richard J.; Yan, Bernard; Bush, Steven J.; Dewey, Helen M.; Thijs, Vincent; Scroop, Rebecca; Simpson, Marion; Brooks, Mark; Asadi, Hamed; Wu, Teddy Y.; Shah, Darshan G.; Wijeratne, Tissa; Ang, Timothy; Miteff, Ferdinand; Levi, Christopher R.; Rodrigues, Edrich; Zhao, Henry; Salvaris, Patrick; Garcia-Esperon, Carlos; Bailey, Peter; Rice, Henry; de Villiers, Laetitia; Brown, Helen; Redmond, Kendal; Leggett, David; Fink, John N.; Collecutt, Wayne; Wong, Andrew A.; Muller, Claire; Coulthard, Alan; Mitchell, Ken; Clouston, John; Mahady, Kate; Field, Deborah; Ma, Henry; Phan, Thanh G.; Chong, Winston; Chandra, Ronil V.; Slater, Lee-Anne; Krause, Martin; Harrington, Timothy J.; Faulder, Kenneth C.; Steinfort, Brendan S.; Bladin, Christopher F.; Sharma, Gagan; Desmond, Patricia M.; Parsons, Mark W.; Donnan, Geoffrey A.; Davis, Stephen M. (2018). "Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke". New England Journal of Medicine. 378 (17): 1573–1582. doi:10.1056/NEJMoa1716405. ISSN 0028-4793.
  15. ↑ Jeong, Han-Gil; Kim, Beom Joon; Yang, Mi Hwa; Han, Moon-Ku; Bae, Hee-Joon; Lee, Seung-Hoon (2016). "Stroke outcomes with use of antithrombotics within 24 hours after recanalization treatment". Neurology. 87 (10): 996–1002. doi:10.1212/WNL.0000000000003083. ISSN 0028-3878.
  16. ↑ "The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group". Lancet. 349 (9065): 1569–81. May 1997. PMID 9174558.
  17. ↑ Zinkstok, Sanne M; Roos, Yvo B (2012). "Early administration of aspirin in patients treated with alteplase for acute ischaemic stroke: a randomised controlled trial". The Lancet. 380 (9843): 731–737. doi:10.1016/S0140-6736(12)60949-0. ISSN 0140-6736.
  18. ↑ Johnston, S. Claiborne; Easton, J. Donald; Farrant, Mary; Barsan, William; Conwit, Robin A.; Elm, Jordan J.; Kim, Anthony S.; Lindblad, Anne S.; Palesch, Yuko Y. (2018). "Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA". New England Journal of Medicine. 379 (3): 215–225. doi:10.1056/NEJMoa1800410. ISSN 0028-4793.
  19. ↑ 19.0 19.1 19.2 19.3 19.4 19.5 Jauch EC, Saver JL, Adams HP, Bruno A, Connors JJ, Demaerschalk BM; et al. (2013). "Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association". Stroke. 44 (3): 870–947. doi:10.1161/STR.0b013e318284056a. PMID 23370205.
  20. ↑ Lansberg MG, O'Donnell MJ, Khatri P, Lang ES, Nguyen-Huynh MN, Schwartz NE; et al. (2012). "Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines". Chest. 141 (2 Suppl): e601S–36S. doi:10.1378/chest.11-2302. PMC 3278065. PMID 22315273.
  21. ↑ "Position Statement on the Use of Intravenous Thrombolytic Therapy in the Treatment of Stroke". American Academy of Emergency Medicine. Retrieved 2008-01-25.
  22. ↑ Prabhakaran S, Ruff I, Bernstein RA (2015). "Acute stroke intervention: a systematic review". JAMA. 313 (14): 1451–62. doi:10.1001/jama.2015.3058. PMID 25871671.
  23. ↑ Wardlaw JM, Murray V, Berge E, del Zoppo GJ (2014). "Thrombolysis for acute ischaemic stroke". Cochrane Database Syst Rev. 7: CD000213. doi:10.1002/14651858.CD000213.pub3. PMC 4153726. PMID 25072528.
  24. ↑ Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E; et al. (2014). "Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials". Lancet. doi:10.1016/S0140-6736(14)60584-5. PMID 25106063.
  25. ↑ Paciaroni M, Agnelli G, Micheli S, Caso V (2007). "Efficacy and safety of anticoagulant treatment in acute cardioembolic stroke: a meta-analysis of randomized controlled trials". Stroke. 38 (2): 423–30. doi:10.1161/01.STR.0000254600.92975.1f. PMID 17204681. ACP JC synopsis
  26. ↑ Hart RG, Pearce LA, Aguilar MI (2007). "Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation". Ann. Intern. Med. 146 (12): 857–67. PMID 17577005.
  27. ↑ Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K; et al. (2019). "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–e418. doi:10.1161/STR.0000000000000211. PMID 31662037.
  28. ↑ Kleindorfer DO, Towfighi A, Chaturvedi S, Cockroft KM, Gutierrez J, Lombardi-Hill D; et al. (2021). "2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association". Stroke. 52 (7): e364–e467. doi:10.1161/STR.0000000000000375. PMID 34024117 Check |pmid= value (help).


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