Is intravenous tenecteplase appropriate for wake‑up acute ischemic stroke patients, and what imaging criteria and dosing should be used?

Tenecteplase for Wake-Up Stroke: Current Evidence and Recommendations

For patients who wake up with stroke symptoms, intravenous tenecteplase is NOT currently recommended outside of clinical trials when selection is based on non-contrast CT alone, but MAY be considered as a reasonable alternative to alteplase when patients are selected using advanced imaging (DWI-FLAIR mismatch or perfusion imaging). 1

Evidence-Based Recommendations by Selection Method

Non-Contrast CT Selection (Standard Imaging)

• The European Stroke Organisation strongly recommends AGAINST using tenecteplase 0.25 mg/kg for wake-up stroke patients selected with non-contrast CT alone (low evidence, strong recommendation). 1
• This recommendation reflects insufficient safety and efficacy data for this specific population when advanced imaging is not used. 1
• The TWIST trial is currently investigating this exact question—tenecteplase versus standard care in wake-up stroke patients selected by non-contrast CT within 4.5 hours of awakening—but results are not yet available. 2

Advanced Imaging Selection (DWI-FLAIR Mismatch or Perfusion)

• The European Stroke Organisation provides an expert consensus statement that tenecteplase 0.25 mg/kg may be a reasonable alternative to alteplase 0.9 mg/kg for wake-up stroke patients who are IVT-eligible after selection with advanced imaging. 1
• The WAKE-UP trial demonstrated that alteplase administered to wake-up stroke patients selected by DWI-FLAIR mismatch significantly improved functional outcomes (mRS 0-1: 53.3% vs 41.8%, adjusted OR 1.61,95% CI 1.06-2.36, p=0.02), establishing the validity of this imaging-based approach. 3
• Given the proven non-inferiority of tenecteplase 0.25 mg/kg to alteplase 0.9 mg/kg in standard time-window patients, extrapolation to wake-up stroke selected by advanced imaging is biologically plausible. 1, 4

Imaging Criteria for Wake-Up Stroke Thrombolysis

MRI-Based Selection (Preferred)

• Use DWI-FLAIR mismatch as the selection criterion: visible acute ischemia on diffusion-weighted imaging (DWI) with no corresponding hyperintensity on FLAIR sequences. 3
• This pattern indicates stroke onset likely within 4.5 hours, as FLAIR changes typically appear 3-4.5 hours after symptom onset. 3
• Treatment must be initiated within 4.5 hours of awakening or discovery of symptoms. 3

CT Perfusion-Based Selection (Alternative)

• For patients presenting 6-24 hours after last known well with large vessel occlusion, use CT perfusion or DW-MRI to determine eligibility, applying DAWN or DEFUSE-3 criteria. 3
• DAWN criteria: NIHSS ≥10 with core infarct 0-21 mL (if >80 years) or 0-31 mL (if <80 years), OR NIHSS ≥20 with core 31-<51 mL (if <80 years). 3
• DEFUSE-3 criteria: Core volume <70 mL, mismatch ratio ≥1.8, and mismatch volume ≥15 mL. 3

Dosing Protocol for Tenecteplase

Standard Dose (When Used)

• Administer tenecteplase 0.25 mg/kg as a single intravenous bolus over 5-10 seconds. 1
• Maximum dose: 25 mg (use stroke-specific 25 mg vials to minimize dosing errors). 4
• This dose has demonstrated non-inferiority to alteplase 0.9 mg/kg in multiple randomized trials. 1, 5

Contraindicated Dose

• Do NOT use tenecteplase 0.40 mg/kg—this higher dose is associated with increased hemorrhagic risk without additional benefit. 1

Practical Algorithm for Wake-Up Stroke Management

Step 1: Establish Time Window

• Confirm patient woke up with symptoms or symptoms were discovered upon awakening. 3
• Verify treatment can be initiated within 4.5 hours of awakening. 3

Step 2: Obtain Imaging

• Perform immediate non-contrast CT to exclude hemorrhage. 3
• If MRI is rapidly available, obtain DWI and FLAIR sequences. 3
• If large vessel occlusion is suspected (NIHSS ≥6), obtain CTA from aortic arch to vertex. 3

Step 3: Apply Selection Criteria

• If DWI-FLAIR mismatch is present: Patient is eligible for thrombolysis with either alteplase OR tenecteplase 0.25 mg/kg. 1, 3
• If only non-contrast CT is available: Current guidelines recommend AGAINST tenecteplase; consider enrollment in TWIST trial if available. 1, 2
• If presenting >6 hours with large vessel occlusion: Use CT perfusion or DW-MRI to apply DAWN/DEFUSE-3 criteria for thrombectomy eligibility. 3

Step 4: Administer Thrombolytic (If Eligible)

• Give tenecteplase 0.25 mg/kg as single IV bolus OR alteplase 0.9 mg/kg (10% bolus over 1 minute, 90% over 60 minutes). 1, 6
• Ensure blood pressure <185/110 mmHg before treatment. 6
• Verify glucose >50 mg/dL. 6

Step 5: Proceed to Thrombectomy (If LVO Present)

• Do NOT delay mechanical thrombectomy to assess thrombolytic response. 6
• Administer IV thrombolytic even when thrombectomy is planned. 6

Safety Considerations

Hemorrhagic Risk

• The WAKE-UP trial showed increased parenchymal hemorrhage type 2 with alteplase (4% vs 0.4%, adjusted OR 10.46,95% CI 1.32-82.77), though confidence intervals were wide due to early trial termination. 3
• Tenecteplase 0.25 mg/kg demonstrates similar symptomatic ICH rates to alteplase in standard time-window patients (approximately 2.4-6.4%). 5, 1

Common Pitfalls to Avoid

• Do NOT use non-contrast CT alone to select wake-up stroke patients for tenecteplase—this approach lacks supporting evidence and is explicitly recommended against. 1
• Do NOT withhold thrombolysis from wake-up stroke patients who meet DWI-FLAIR mismatch criteria—this population has proven benefit from alteplase, and tenecteplase is a reasonable alternative. 3, 1
• Do NOT use tenecteplase 0.40 mg/kg—only the 0.25 mg/kg dose is recommended. 1
• Do NOT delay treatment to obtain perfusion imaging in patients presenting within 4.5 hours of awakening with DWI-FLAIR mismatch—this imaging is unnecessary when MRI mismatch criteria are met. 3

Current Guideline Landscape

The 2018 AHA/ASA guidelines recommend AGAINST using imaging criteria to select wake-up stroke patients for IV alteplase outside clinical trials (Class III: No Benefit, Level B-NR). 3 However, this recommendation predates the WAKE-UP trial publication and the recent tenecteplase evidence. The 2023 European Stroke Organisation expedited recommendation provides more current guidance, acknowledging that tenecteplase may be reasonable for wake-up stroke when advanced imaging is used, while strongly recommending against its use with non-contrast CT selection alone. 1