What is the recommended intravenous tenecteplase dosing, contraindications, monitoring, and alternative therapy for acute ischemic stroke patients eligible for treatment within 4.5 hours of symptom onset?

Tenecteplase in Acute Ischemic Stroke

Recommended Dosing and Administration

Tenecteplase 0.25 mg/kg (maximum 25 mg) administered as a single intravenous bolus is a reasonable alternative to alteplase for acute ischemic stroke patients within 4.5 hours of symptom onset, particularly in those with minor neurological impairment and no major intracranial occlusion. 1

Standard Dosing Protocol

• Dose: 0.25 mg/kg body weight, with a maximum dose of 25 mg 2, 3
• Administration: Single intravenous bolus over 5-10 seconds 1
• Time window: Within 4.5 hours of symptom onset or last known well 1, 2, 3

The key advantage of tenecteplase is single-bolus administration compared to alteplase's 60-minute infusion, which simplifies logistics especially for interhospital transfers. 3

Evidence Supporting Tenecteplase

The most recent high-quality evidence comes from three major trials:

• ATTEST-2 (2024): 1,777 patients demonstrated non-inferiority of tenecteplase 0.25 mg/kg to alteplase 0.9 mg/kg within 4.5 hours, with similar functional outcomes (OR 1.07; 95% CI 0.90-1.27) and comparable safety profiles. 3

• ORIGINAL (2024): 1,465 Chinese patients showed tenecteplase was non-inferior to alteplase, with 72.7% achieving mRS 0-1 versus 70.3% with alteplase (RR 1.03; 95% CI 0.97-1.09), and identical symptomatic ICH rates of 1.2%. 2

The 2018 AHA/ASA guidelines assigned tenecteplase a Class IIb recommendation (may be considered) based on earlier phase II/III data showing similar safety but unclear superiority. 1 However, the 2024 trials provide robust evidence supporting equivalence, making tenecteplase a preferred option given its ease of administration. 3

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Contraindications

Tenecteplase shares identical contraindications to alteplase for acute ischemic stroke. 1, 4

Absolute Contraindications

• Intracranial hemorrhage on non-contrast CT or MRI 4
• Blood pressure ≥185/110 mmHg that cannot be controlled before treatment 4
• Active internal bleeding 1
• Recent intracranial or intraspinal surgery (within 3 months) 1
• History of intracranial hemorrhage 1
• Intracranial neoplasm, arteriovenous malformation, or aneurysm 1
• Current severe uncontrolled hypertension 4

Relative Contraindications

• Early ischemic changes exceeding 1/3 of middle cerebral artery territory on imaging 4, 5
• Blood glucose <60 mg/dL or >400 mg/dL 5
• Recent major surgery or serious trauma (within 14 days) 1
• Gastrointestinal or urinary tract hemorrhage within 21 days 1
• Arterial puncture at non-compressible site within 7 days 1

Special Population Considerations

The 2018 AHA/ASA guidelines note that the largest tenecteplase trial (1,100 subjects) excluded patients >80 years old, those with baseline NIHSS >25, those taking oral anticoagulants regardless of INR, and those with both prior stroke and diabetes. 1 However, the 2024 ATTEST-2 and ORIGINAL trials did not have these strict exclusions, suggesting broader applicability. 2, 3

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Monitoring Requirements

Pre-Treatment Monitoring

• Blood pressure: Must be <185/110 mmHg before initiating treatment 4
• Neuroimaging: Non-contrast CT or MRI to exclude hemorrhage and assess early ischemic changes 4
• Laboratory: Blood glucose, coagulation parameters if anticoagulant use suspected 5

Post-Treatment Monitoring

• Blood pressure control: Maintain <180/105 mmHg for at least 24 hours after treatment 4
• Neurological assessments: Frequent monitoring for neurological deterioration, particularly in first 24 hours 1
• Hemorrhage surveillance: Clinical assessment for signs of intracranial or systemic bleeding 2, 3
• Antithrombotic avoidance: No antiplatelet or anticoagulant therapy for 24 hours post-thrombolysis 4

The symptomatic ICH rate with tenecteplase 0.25 mg/kg ranges from 1.2% to 3.0% across recent trials, comparable to alteplase. 2, 3, 6

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Alternative Therapy: Alteplase

Alteplase 0.9 mg/kg (maximum 90 mg) remains the FDA-approved standard thrombolytic agent for acute ischemic stroke within 4.5 hours. 1, 4

Alteplase Dosing

• Total dose: 0.9 mg/kg body weight, maximum 90 mg 4
• Initial bolus: 10% of calculated dose IV push over 1 minute 4
• Infusion: Remaining 90% infused over 60 minutes 4

When to Choose Alteplase Over Tenecteplase

• Regulatory approval: Alteplase has FDA approval for acute ischemic stroke; tenecteplase does not currently have this specific indication in the United States 1
• Institutional protocols: If hospital formulary or protocols have not yet adopted tenecteplase 3
• Large vessel occlusion with planned thrombectomy: While both agents are acceptable, some centers may prefer alteplase based on historical thrombectomy trial data 1

The 2018 AHA/ASA guidelines emphasize that patients eligible for IV thrombolysis should receive it immediately, even if endovascular thrombectomy is being considered, and observation after IV thrombolysis to assess clinical response before thrombectomy is harmful. 1

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Extended Time Window Considerations (4.5-24 Hours)

For patients presenting beyond 4.5 hours, advanced neuroimaging selection is required, and the evidence for tenecteplase versus alteplase differs.

Tenecteplase Beyond 4.5 Hours

Recent data suggest potential benefit but with important caveats:

• TRACE-III (2024): In Chinese patients with large vessel occlusion treated 4.5-24 hours after onset (most without thrombectomy access), tenecteplase 0.25 mg/kg resulted in 33.0% achieving mRS 0-1 versus 24.2% with standard care (RR 1.37; 95% CI 1.04-1.81), but symptomatic ICH was 3.0% versus 0.8%. 6

• Pooled registry data (2025): Comparing tenecteplase to alteplase in patients last known well >4.5 hours showed no significant difference in mRS 0-1 (32.9% vs 37.2%), but tenecteplase was associated with higher rates of any ICH (PSOW-OR 1.79; 95% CI 1.25-2.57) though not symptomatic ICH. 7

Alteplase Beyond 4.5 Hours

The World Stroke Organization recommends considering IV alteplase for patients 4.5-9 hours after onset with CT or MRI perfusion mismatch, specifically when mechanical thrombectomy is not indicated or planned. 5 This approach is supported by the WAKE-UP trial showing benefit with DWI-FLAIR mismatch selection. 1

Critical distinction: The extended window evidence for alteplase is stronger than for tenecteplase. 5, 7 If treating beyond 4.5 hours with advanced imaging selection, alteplase should be preferred unless the patient lacks thrombectomy access and has large vessel occlusion (TRACE-III scenario). 6

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Practical Algorithm for Agent Selection

Within 4.5 Hours of Onset

1. Confirm eligibility: Acute ischemic stroke, no contraindications, BP controlled <185/110 mmHg 4
2. Obtain non-contrast CT: Exclude hemorrhage, assess early ischemic changes 4
3. Choose thrombolytic:
   • Tenecteplase 0.25 mg/kg if available and institutional protocols permit (preferred for ease of administration) 3
   • Alteplase 0.9 mg/kg if tenecteplase unavailable or not yet adopted 4
4. Administer immediately: Do not delay for vascular imaging if thrombectomy not immediately planned 1

Beyond 4.5 Hours (4.5-24 Hours)

1. Obtain advanced imaging: CT or MRI perfusion to assess core/penumbra mismatch 5
2. Assess for large vessel occlusion: CT angiography 5
3. Determine thrombectomy eligibility: If eligible, proceed to thrombectomy (may give alteplase en route) 1
4. If thrombectomy not indicated/available:
   • Alteplase 0.9 mg/kg preferred for 4.5-9 hour window with perfusion mismatch 5
   • Tenecteplase 0.25 mg/kg may be considered for large vessel occlusion without thrombectomy access, accepting higher ICH risk 6

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Common Pitfalls and How to Avoid Them

Pitfall 1: Delaying Treatment for Vascular Imaging

Avoid: Patients eligible for IV thrombolysis within 4.5 hours should receive treatment before obtaining CT angiography or transferring for thrombectomy. 1 Observation after thrombolysis to assess response before thrombectomy is harmful. 1

Pitfall 2: Using Tenecteplase Beyond 4.5 Hours Without Appropriate Selection

Avoid: The extended window data for tenecteplase are limited and show concerning ICH signals. 7, 6 Use alteplase with perfusion imaging selection for 4.5-9 hour window unless specific TRACE-III criteria met. 5, 6

Pitfall 3: Incorrect Tenecteplase Dosing

Avoid: The evidence supports 0.25 mg/kg (maximum 25 mg), not the 0.4 mg/kg dose mentioned in earlier 2018 guidelines for minor stroke. 1, 2, 3 The 0.4 mg/kg dose failed to show superiority and is not the recommended dose. 1

Pitfall 4: Administering Antiplatelet Therapy Too Early

Avoid: Wait 24 hours after thrombolysis before starting aspirin or other antithrombotic agents. 4 Early aspirin within 24 hours increases hemorrhagic complications. 1

Pitfall 5: Inadequate Blood Pressure Control

Avoid: Blood pressure must be <185/110 mmHg before treatment and maintained <180/105 mmHg for 24 hours after. 4 Failure to control BP increases hemorrhagic transformation risk substantially.