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).


For summary of all the guidelines with side to side comparison of all the guidelines please refer here, Summary and evolution of AIS guidelines.

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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