Ischemic stroke medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Hasnain Ali Moryani, MBBS[2] Aysha Anwar, M.B.B.S[3]

Overview

Medical Therapy

Initial Management

  • Treatment of COVID-19–associated ischemic stroke generally follows standard acute ischemic stroke pathways.
  • In patients with suspected or confirmed LVO, evaluation for EVT should occur urgently, and IV thrombolysis should be given when eligible without delaying EVT.
  • EVT indications include appropriately selected patients within 0–6 hours, and in selected patients within 6–24 hours based on imaging/clinical criteria; recent randomized trials also support EVT in selected large ischemic core anterior circulation strokes (ASPECTS 3–5) and basilar artery occlusion.[8][9][10]
  • 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.[11]
  • The use of thrombolysis via ultrasound waves concomitant to IV fibrinolysis is not recommended.[12]

Medical Therapy

Alteplase

Tenecteplase

  • Tenecteplase (0.25 mg/kg IV bolus; max 25 mg) is recommended as an equivalent alternative to alteplase for IV thrombolysis in eligible acute ischemic stroke patients presenting within 4.5 hours of symptom onset (COR 1, 2026 AHA/ASA). Tenecteplase received FDA approval for acute ischemic stroke in 2025.[20]
  • Multiple large phase III randomized controlled trials (AcT, n=1600; ATTEST-2, n=1777; ORIGINAL, n=1465; TRACE-2, n=1430) have individually demonstrated noninferiority of tenecteplase 0.25 mg/kg versus alteplase for the primary outcome of mRS 0–1 at 90 days, with similar safety profiles:
    • AcT: risk difference 2.1% (95% CI, −2.6 to 6.9)
    • ATTEST-2: risk difference 1.99% (95% CI, −2.77 to 6.75)
    • ORIGINAL: adjusted risk difference 2.12% (95% CI, −2.17 to 6.40)
  • A systematic review and meta-analysis of 11 RCTs demonstrated that tenecteplase was superior to alteplase for excellent functional outcome (mRS 0–1) with similar rates of symptomatic intracerebral hemorrhage and mortality.[21]
  • Tenecteplase at a dose of 0.40 mg/kg is not recommended due to no additional benefit and potential for harm (COR 3: Harm).
  • Among patients with LVO planned for thrombectomy, tenecteplase (0.25 mg/kg) achieved higher early reperfusion than alteplase (22% vs 10%) and improved 90-day functional outcome (median mRS 2 vs 3) with similar symptomatic ICH (1% vs 1%) in EXTEND-IA TNK.[22]
  • Tenecteplase has also shown benefit in selected patients treated 4.5–24 hours after onset when thrombectomy is not available, in patients with salvageable ischemic penumbra on perfusion imaging (TRACE-III).[23]
Thrombolytic Agent Dose Administration Key Evidence
Alteplase 0.9 mg/kg (max 90 mg) 10% bolus over 1 min, remainder infused over 60 min Standard of care since 1995; NNT 10 within 3 h, NNT 19 from 3–4.5 h
Tenecteplase 0.25 mg/kg (max 25 mg) Single IV bolus over 5–10 seconds Noninferior to alteplase in AcT, ATTEST-2, ORIGINAL, TRACE-2; FDA approved 2025
Tenecteplase 0.4 mg/kg Not recommended — no additional benefit and potential for harm (COR 3: Harm)

Endovascular Thrombectomy

  • EVT is recommended for patients with AIS from anterior circulation proximal LVO (ICA or M1), presenting within 6 hours from onset, with NIHSS score ≥6, prestroke mRS 0–1, and ASPECTS 3–10 (COR 1).
  • In selected patients with anterior circulation proximal LVO presenting between 6 and 24 hours, with age <80 years and appropriate imaging criteria, EVT is recommended.
  • For patients with ASPECTS 0–2 within 6 hours (age <80 years), EVT may be considered in selected cases.
  • The ATLAS individual patient data meta-analysis of 6 large-core trials confirmed EVT benefit up to core volume of 150 mL, with NNT of 4.2 for ≥1 mRS point improvement and NNT of 8.6 for functional independence. EVT recipients more than doubled their rate of functional independence compared with medical therapy alone (approximately 21% vs 9%).
  • For patients with prestroke mRS of 2 presenting within 6 hours with NIHSS ≥6 and ASPECTS ≥6, EVT is reasonable (COR 2a).
Posterior Circulation
  • In patients with AIS from basilar artery occlusion, baseline mRS 0–1, NIHSS ≥10, and PC-ASPECTS ≥6, EVT within 24 hours is recommended (COR 1), based on the ATTENTION and BAOCHE trials.
  • The VERITAS individual patient data meta-analysis of 4 RCTs (BEST, BASICS, ATTENTION, BAOCHE) demonstrated EVT benefit for basilar artery occlusion (adjusted cOR 2.41, 95% CI 1.78–3.26) with reduced mortality (OR 0.60).[24]
IVT Before EVT
  • In patients eligible for both IV thrombolysis and EVT, IV thrombolysis should be administered without delaying EVT. The IRIS meta-analysis demonstrated a time-dependent benefit of IVT before EVT, with significant benefit when onset-to-IVT time was short.[25]
  • IV thrombolysis should not be withheld in EVT-eligible patients solely because EVT is planned, unless the patient is already in the angiography suite and EVT can be initiated immediately.

Antiplatelet Therapy

Dual Antiplatelet Therapy (DAPT)
  • Dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel should be started early (ideally within 24 hours) and continued short term (commonly ~21 days) in patients with minor noncardioembolic ischemic stroke (NIHSS ≤3) or high-risk TIA (ABCD2 ≥4) who did not receive IV thrombolysis, followed by single antiplatelet therapy (SAPT).[29] The benefit of DAPT is confined to the first 21 days, as demonstrated by the CHANCE-POINT pooled analysis (HR 0.66, 95% CI 0.56–0.77).[30]
  • In patients with recent stroke/TIA attributable to severe symptomatic intracranial stenosis (intracranial atherosclerotic disease, ICAD), DAPT for up to 90 days is reasonable.
  • The INSPIRES trial extended the evidence for DAPT (aspirin + clopidogrel × 21 days) to patients with minor stroke (NIHSS ≤5) or TIA with presumed atherosclerosis presenting within 72 hours (NNT 53).[31]
Trial Population DAPT Regimen Duration Key Result (NNT)
CHANCE Minor stroke (NIHSS ≤3) or high-risk TIA (ABCD2 ≥4); within 24 h Clopidogrel + aspirin 21 days Reduced recurrent stroke; NNT 28[32]
POINT Minor stroke (NIHSS ≤3) or high-risk TIA (ABCD2 ≥4); within 12 h Clopidogrel + aspirin 90 days Reduced ischemic events; NNT 67; stopped early for excess major bleeding[33]
THALES Minor stroke (NIHSS ≤5) or high-risk TIA; within 24 h Ticagrelor + aspirin 30 days Reduced stroke/death; NNT 91; increased fatal bleeding[34]
CHANCE-2 CYP2C19 LOF carriers; minor stroke or TIA; within 24 h Ticagrelor + aspirin 21 days Superior to clopidogrel + aspirin in LOF carriers; NNT 63[35]
INSPIRES Minor stroke (NIHSS ≤5) or TIA with presumed atherosclerosis; within 72 h Clopidogrel + aspirin 21 days Reduced recurrent stroke; NNT 53

Anticoagulation

  • In patients with ischemic stroke and atrial fibrillation, early initiation of DOACs (within ≤4 days of stroke onset) is supported by the CATALYST individual patient data meta-analysis of 4 RCTs (TIMING, ELAN, OPTIMAS, START; n=5441), which demonstrated a reduced composite outcome (OR 0.70, 95% CI 0.50–0.98, p=0.039) and reduced recurrent ischemic stroke (OR 0.66, 95% CI 0.45–0.96) without increased symptomatic intracerebral hemorrhage.[5]
  • The ELAN trial (n=2013) compared early (within 48 hours for minor/moderate stroke; within 6–7 days for major stroke) versus later DOAC initiation and found a primary composite outcome of 2.9% in the early group versus 4.1% in the later group (risk difference −1.18 percentage points, 95% CI −2.84 to 0.47).[37]
  • The OPTIMAS trial (n=3621) confirmed noninferiority of early (≤4 days) versus delayed (7–14 days) DOAC initiation.[38]
  • In patients with stroke at high risk of hemorrhagic conversion (eg, large infarct volume), it remains reasonable to delay initiation of oral anticoagulation beyond 14 days to reduce the risk of intracerebral hemorrhage.

Blood Pressure Management

Pre-Thrombolysis
  • Blood pressure should be lowered to <185/110 mmHg before IV thrombolysis.
Post-Thrombolysis
  • Blood pressure should be maintained <180/105 mmHg for the first 24 hours after IV thrombolysis.
Post-EVT
Patients Not Receiving Thrombolysis or EVT
  • In patients with BP ≥220/120 mmHg who do not receive IV thrombolysis or EVT, it may be reasonable to lower BP by 15% during the first 24 hours.
  • In patients with BP <220/120 mmHg who do not receive IV thrombolysis or EVT, initiating or restarting antihypertensive treatment within the first 48–72 hours is generally safe.

Glucose Management

  • Hyperglycemia (>180 mg/dL) should be treated during the first 24 hours after ischemic stroke, targeting glucose levels of 140 to 180 mg/dL.
  • Intensive glucose control (80–130 mg/dL) with IV insulin is not recommended (COR 3: No Benefit), as it has not been shown to improve outcomes and may increase the risk of hypoglycemia.
  • Hypoglycemia (<60 mg/dL) should be treated promptly.

Statin Therapy

  • High-intensity statin therapy should be initiated in patients younger than 75 years with clinical ASCVD, to achieve 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.[40]
  • Risks and benefits should be discussed before initiation of statin therapy to weigh ASCVD risk reduction against the potential for statin-associated side effects.
  • Continuation of statin therapy during the acute period of ischemic stroke is reasonable among patients already taking statins.
  • For secondary prevention, the target LDL-C is <70 mg/dL for atherosclerotic stroke.

Summary Table: Acute Medical Therapy

Medical treatment Drug class Recommendations
Acute Long-Term
Reperfusion therapy IV thrombolysis (alteplase or tenecteplase); Endovascular thrombectomy (EVT)

IV alteplase or tenecteplase in eligible patients within ≤4.5 h (COR 1)

Tenecteplase 0.25 mg/kg IV bolus (max 25 mg) is an accepted equivalent alternative to alteplase

Evaluate urgently for EVT in eligible LVO patients; do not delay EVT for thrombolysis completion

EVT for anterior LVO within 6 h (ASPECTS 3–10) and 6–24 h (ASPECTS 3–5, age <80)

EVT for basilar artery occlusion within 24 h (NIHSS ≥10, PC-ASPECTS ≥6) (COR 1)

None

Antithrombotic agents Antiplatelet agents

Oral aspirin (initial dose 160–325 mg) within 24–48 h after stroke onset; delay 24 h after IV thrombolysis

DAPT (aspirin + clopidogrel × 21 days) for minor noncardioembolic stroke (NIHSS ≤3) or high-risk TIA (ABCD2 ≥4) not treated with IV thrombolysis (COR 1)

DAPT for up to 90 days is reasonable for stroke/TIA attributable to severe symptomatic intracranial stenosis (ICAD)

Long-term SAPT with clopidogrel 75 mg, aspirin 50–325 mg, or aspirin 25 mg/extended-release dipyridamole 200 mg twice daily for secondary prevention of noncardioembolic stroke

Anticoagulants

Parenteral or oral anticoagulation is not recommended within 48 h of onset in the general population

For AF-related stroke: early DOAC initiation (≤4 days) is supported by CATALYST meta-analysis (OR 0.70 for composite outcome)

Delay anticoagulation beyond 14 days for strokes at high risk of hemorrhagic conversion

DOACs (apixaban, dabigatran, edoxaban, rivaroxaban) preferred over warfarin for nonvalvular AF (COR 1)

Warfarin for valvular AF (moderate-severe mitral stenosis or mechanical valve)

Antilipid therapy Statins

Continue statin therapy during the acute period in patients already taking statins

High-intensity statin therapy for atherosclerotic stroke; target LDL-C <70 mg/dL

Antihypertensive therapy Intravenous antihypertensives

(Labetalol, nicardipine, clevidipine)

Lower BP to <185/110 mmHg before IV thrombolysis

Maintain BP <180/105 mmHg for 24 h after IV thrombolysis

Maintain BP ≤180/105 mmHg post-EVT; intensive SBP <120 mmHg may be harmful

Long-term oral antihypertensives for secondary prevention; target <130/80 mmHg

Oral antihypertensive therapy

Restarting antihypertensives within 48–72 h in patients with BP <220/120 mmHg is generally safe

Long-term oral antihypertensives for secondary prevention in patients with history of hypertension

Antihyperglycemic agents Insulin

Treat hyperglycemia to target glucose 140–180 mg/dL

Intensive glucose control (80–130 mg/dL) with IV insulin is not recommended (COR 3: No Benefit)

Long-term oral antidiabetic therapy for secondary prevention in patients with diabetes mellitus; target HbA1c <7%

Long-Term Management

Secondary Prevention — Antithrombotic Therapy

Secondary Prevention — Risk Factor Management

  • Target LDL-C <70 mg/dL for atherosclerotic stroke.
  • Target blood pressure <130/80 mmHg for secondary prevention.
  • Target HbA1c <7% for patients with diabetes.

Special Populations

CYP2C19 Loss-of-Function Carriers

  • In patients with minor stroke or high-risk TIA who are CYP2C19 loss-of-function carriers, ticagrelor plus aspirin for 21 days is superior to clopidogrel plus aspirin (CHANCE-2; NNT 63).[35]
  • CYP2C19 genotyping may be considered to guide antiplatelet selection in patients with minor stroke or high-risk TIA when results can be obtained rapidly.

Patients With Intracranial Atherosclerotic Disease (ICAD)

  • 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 (COR 1).
  • 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 (COR 2a).
  • Maintenance of SBP below 140 mmHg, high-intensity statin therapy, and at least moderate physical activity are recommended (COR 1).

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[41]

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[42]

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

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